Friday, October 6, 2017

Amgen v. Sanofi

The Federal Circuit has not been kind to patents that claim antibodies by the structure of an antigen/epitope without specifying the antibody structure.  Yesterday, the Fed. Cir. found the jury instructions in Amgen v. Sanofi  that "in the case of a claim to antibodies, the correlation between structure and function may also be satisfied by the disclosure of a newly characterized antigen" to be erroneous since "The essential problem with the jury instruction given in this case is that it effectively permitted the jury to dispense with the required finding of a written description of the invention."  In a previous case, the Fed. Cir. found the term “anti-CD20 antibody” to be limited to the particular epitope on CD20 that Biogen’s antibody bound.  Another Fed. Cir. case found the claim "a neutralizing isolated human antibody, or antigen-binding portion thereof that binds to human IL-12 . . ." to be invalid for written description.  The Federal Circuit’s decisions are in conflict with the USPTO’s written description guidelines that allow claiming an antibody to a specific antigen even if the specification does not disclose a specific antibody that binds to the particular antigen.

https://lnkd.in/gbr9ATG

And I was taking a break!

Thursday, October 5, 2017

Taking a break

I will be taking a six months break from this blog to focus on starting a blog on cryptocurrency.  I appreciate the many views that I have received so far.  As always, feel free to send me pharma patent work.

Thursday, August 31, 2017

Sandoz Files IPR Peitions Against Humira Ulcerative Colitis and Crohn's Disease Patents

On August 21, 2017, Sandoz filed two IPR petitions against Humira patents claiming a method for treating ulcerative colitis or Crohn's disease with a total body dose of 40 mg of Humira.  Sandoz argues that these patents are invalid based on the PTAB’s decision that invalidated a similar Humira method patent claiming the same dose for treating rheumatoid arthritis.

IPR2017-01988
8,974,790
1. A method for treating ulcerative colitis in a human subject, comprising administering subcutaneously to a human subject having ulcerative colitis a total body dose of 40 mg of a human anti-TNFα antibody once every 13-15 days for a time period sufficient to treat the ulcerative colitis, wherein the anti- TNFα antibody comprises [Humira].
IPR2017-01987
8,911,737
1. A method for treating Crohn's disease in a human subject, comprising administering subcutaneously to a human subject having Crohn's disease a total body dose of 40 mg of a human anti-TNF.alpha. antibody once every 13-15 days for a time period sufficient to treat Crohn's disease, wherein the anti- TNFα antibody comprises [Humira].


IPR2016-00172
8,889,135
Invalidated by the PTAB
1. A method for treating rheumatoid arthritis in a human subject, comprising administering subcutaneously to a human subject having rheumatoid arthritis a total body dose of 40 mg of a human anti- TNFα antibody once every 13 -15 days for a time period sufficient to treat the rheumatoid arthritis, wherein the anti- TNFα antibody comprises [Humira].

Sandoz argues that the only difference between claim 1 of these patents and claim 1 of the ’135 patent invalidated by the Board is the substitution of “ulcerative colitis” or “Crohn's disease” for “rheumatoid arthritis.” According to Sandoz, the prior art (Salfeld) taught that Humira was useful to treat UC, Crohn’s disease, and RA with a dosage range applicable to all three indications.   In fact, the only disclosure in the patents that relates to UC or Crohn's disease was lifted directly from Salfeld. 

Friday, August 11, 2017

Amgen v. Hospira

Federal Circuit:  [O]nce a patent is listed by the sponsor, the BPCIA’s (Biologics Price Competition and Innovation Act) information exchange further requires the applicant to “provide to the . . . sponsor, with respect to each patent listed . . . a detailed statement that describes, on a claim by claim basis, the factual and legal basis of the opinion of the subsection (k) applicant that such patent is invalid, unenforceable, or will not be infringed.” 42 U.S.C. § 262(l)(3)(B)(ii) In other words, once a sponsor lists a patent under paragraph (l)(3)(A), the applicant must once again come forward with additional disclosures under paragraph (l)(3)(B) that inform whether “a claim of patent infri http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/16-2179.Opinion.8-8-2017.1.PDFngement . . . could” or could not “reasonably be asserted.” If the applicant fails to comply with its obligation to respond under paragraph (l)(3)(B), the sponsor would have a reasonable basis for asserting a claim of patent infringement. . . Thus, if a sponsor forms a belief based on an inquiry limited by an applicant’s withholding of information, the sponsor has still satisfied Rule 11.

These considerations dispel the notion that Amgen would have needed to bring suit simply based on its own unsupported belief. Hospira, in fact, agrees that Amgen could have validly listed its cell-culture patents under paragraph (l)(3)(A) and that Hospira would have been obligated to respond with “detailed statement[s]” under paragraph (l)(3)(B). In this scenario, Amgen would have had an opportunity to assess the reasonableness of its litigation position long before filing suit and being exposed to Rule 11 sanctions or antitrust liability. Thus, the reasonableness requirement of paragraph (l)(3)(A) does not preclude a sponsor from listing a patent for which an applicant has not provided information under paragraph (l)(2)(A).5 The denial of discovery in this case does not undermine the purpose of the BPCIA.

The district court correctly denied Amgen’s motion to compel on the ground that the composition of Hospira’s cell-culture media was of “no relevance to the patents that are asserted.” J.A. 37. Amgen has not established a clear and indisputable right to discovery of the information it seeks. It therefore has not established the prerequisites for this court to issue a writ of mandamus. 

http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/16-2179.Opinion.8-8-2017.1.PDF

Wednesday, August 9, 2017

Free CLE Courses (NY and CA credit) for Pharma Corporate Patent Counsel

I am providing free CLE courses for pharma corporate patent counsel.  The CLE course would be designed specifically for your area of practice.  Please contact me if you are interested.

Tuesday, August 8, 2017

Del. Mag. Judge: Claim Term “Molecular Weight” Is Indefinite

In Integra Lifesciences v. Hyperbranch Medical Technology, the Defendant took the position that the term "molecular weight" in the claims of U.S. Patent 6,566,406 was indefinite:

1. A method for preparing a biocompatible crosslinked polymer hydrogel, comprising: providing a biocompatible small molecule crosslinker with a molecular weight of 2000 or less, the crosslinker having n crosslinker functional groups, wherein n is two or more, and wherein the crosslinker functional groups are either electrophilic or nucleophilic; providing a synthetic biocompatible functional polymer with a molecular weight of at least about 7 times more than the crosslinker. . .

It was undisputed that, when determining the molecular weight of a polymer, different
statistical measures could be used and that these would yield different numerical values for a given polymer.  Defendant relied heavily on the decision of the United States Court of Appeals for the Federal Circuit in Teva Pharms. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335 (Fed. Cir. 2015) in support of its argument, a case that analyzed indefiniteness with respect to the same term.  In Teva, the Federal Circuit held that:

[I]t is undisputed that "molecular weight" or average molecular weight can be ascertained by any of three possible measures: Mp, Mn, and Mw. The claims do not indicate which measure to use.  The specification never defines molecular weight or even mentions Mp, Mw, or Mn. And the term "average molecular weight" does not have a plain meaning to one of skill in the art .... During prosecution of the related patents, which with respect to molecular weight have identical specifications, examiners twice rejected the term "molecular weight" as indefinite for failing to disclose which measure of molecular weight to use (Mp, Mn, or Mw). And the patentee in one instance stated that it was Mw and in the other stated it was Mp . ... We hold that claim 1 is invalid for indefiniteness by clear and convincing evidence because read in light of the specification and the prosecution history, the patentee has failed to inform with reasonable certainty those skilled in the art about the scope of the invention. On this record, there is not reasonable certainty that molecular weight should be measured using Mp.

In this case, the magistrate judge also found that the claim term “molecular weight” was indefinite:

The claims and the specification of the '406 patent do not directly speak to this issue at all. Nor is the Court persuaded that the POSITA would follow [the patentee’s expert’s]  9-step pathway to "Mn" in order to fill in the gap. That pathway relies in significant part on a single citation in the later-issued '705 patent to the Aldrich Catalog. And that very citation, on its face, does not direct anyone to consult the Aldrich Catalog for purposes of assessing measurements of molecular weight. Even if one did turn to the Aldrich Catalog for this purpose, the catalog does nothing to clearly indicate what measurement should be used; instead, it makes reference to different types of molecular weight measurements, a fact that would only solidify a POSITA's uncertainty. All of this, along with Dr. Mays' tendency to cherry-pick (without explanation) which portions of the Aldrich Catalog a POSITA would look to in the first place, renders the outcome here clear. See Butamax Advanced Biofuels, LLC v. Gevo, Inc., 117 F. Supp. 3d 632, 641 (D. Del. 2015) (finding claim indefinite where various methods could have been used to make the calculation called for by the claim limitation at issue, and "[b]ased on the broad and ambiguous language of the specification, the court does not find commonsensible [the expert's] conclusory assertion that a [POSITA] would be directed by the specification to use the MegAlign program (and its online help manual not referred to in the specification)" to do so). The Court agrees with Defendant that this case is similar to Teva, and that the conclusion reached here should be the same as the conclusion the Federal Circuit reached in that case.



Tuesday, August 1, 2017

Send us ANDA/Pharma/Biotech patent work

Send us ANDA/Pharma/Biotech patent work.  We provide flat fee arrangements and two separate attorneys read every opinion before it is signed (attorney advertising).  

Thursday, July 27, 2017

Federal Circuit: Regeneron’s Intent To Deceive the USPTO Is Inferred from Failure to Disclose Relevant Documents During Litigation

After being sued for patent infringement by Regeneron, Merus asserted a counterclaim of unenforceability due to inequitable conduct. Inequitable conduct is an equitable defense to patent infringement that, if proved, bars enforcement of a patent.  Inequitable conduct has two separate requirements: materiality and intent.

There was no question that Regeneron knew about several prior art references and did not disclose them to the Patent Office.  Regeneron, however, took the position that there was no inequitable content because there was no specific intent to withhold the prior art references and that the prior art references were not material. 

During litigation, Regeneron failed to disclose to Merus documents that were relevant to the issue of intent.  “The district court concluded that many documents on the log were directly relevant to the topics as to which privilege has been waived. In particular, these documents were directly relevant to Drs. Smeland and Murphy’s mental impressions of the Withheld References during prosecution of the ’018 patent. The documents would have been relevant to determining if Regeneron specifically intended to deceive the PTO by failing to disclose the Withheld References during prosecution of the ’018 patent.”

The Federal Circuit affirmed the district court’s decision that “it was appropriate to draw an adverse inference against Regeneron from the undisclosed documents. In particular, the district court concluded that Regeneron failed to disclose the Withheld References to the PTO during prosecution of the ’018 patent with the specific intent to deceive the PTO.”

The district court also found (the Federal Circuit did not address this issue) that Regeneron had engaged in affirmative egregious misconduct—an alternative to but-for materiality—based on certain misleading statements Regeneron made to the PTO during prosecution. 

Below is the relevant portion of the Federal Circuit’s decision:
---------------

The district court provided a lengthy list of Dr. Smeland’s problematic assertions to emphasize the seriousness of the issue. In particular, Dr. Smeland stated that:

I firmly believed—and still believe today— that Brüggemann, Taki, Zou and Wood were not material to patentability because they were substantially different from the mice claimed in the ’176 application . . . and were cumulative of other information before the Patent Examiner.”
Dr. Smeland’s description of his understanding of what a materiality analysis for inequitable conduct involves: “Regardless of whether I satisfied the minimum requirements of being an ordinary skilled artisan, I felt comfortable evaluating the art from that perspective during the prosecution of the ’176 application. When I did have questions, however, I did not hesitate to reach out to those with more experience and knowledge.”
“I routinely made Regeneron inventors aware of the foregoing obligations when providing them with invention declarations.”
With regards to Brüggemann and Zou, “I was generally familiar with the subject matter of those two references . . . [a]t no time did I consider these references to be material to patentability to the claims pending in the ’176 application.”
“Because of this experience [prosecuting the ’176 application as well as the ’287 Patent], I was readily familiar with both prior art that was before the Examiner in the ’176 application and the pending claims of the ’176 application.”
“I viewed the analysis [relating to the Withheld References] as straightforward.”
I concluded that [the Withheld References], alone or combined with other prior art of which I was aware, were cumulative of information already before the Examiner. Furthermore, it was my view that the skilled artisan would not have viewed them as teaching the reverse chimeric inventions that the Examiner had allowed in the ’176 application.” Id. at 590–93.

These statements and others implicated Dr. Smeland’s knowledge and state of mind regarding the Withheld References directly—both during prosecution and continuing through to trial. During litigation, Regeneron made a choice to maintain the attorney-client privilege as to Dr. Smeland’s knowledge and thoughts about the Withheld References during prosecution of the ’176 application. In maintaining its assertion of privilege, Regeneron shielded Dr. Smeland’s documents relating to his knowledge and thoughts about the Withheld References during prosecution from disclosure. As with any affirmative disclosure of information otherwise protected by the attorney-client privilege, however, once the disclosure of the trial affidavit was made, as it was not inadvertent, the waiver was complete. See In re von Bulow828 F.2d 94, 102–03 (2d Cir. 1987) (“‘[S]ubject matter waiver’ . . . allows the attacking party to reach all privileged conversations regarding a particular subject once one privileged conversation on that topic has been disclosed.”); see also Fort James Corp. v. Solo Cup Co., 412 F.3d 1340, 1349 (Fed. Cir. 2005) (“The widely applied standard for determining the scope of a waiver of attorney-client privilege is that the waiver applies to all other communications relating to the same subject matter.”). 

Thus, on the day that Regeneron disclosed Dr. Smeland’s trial affidavit, it waived the privilege as to the subject matter of each of the topics the affidavit addressed. In particular, Regeneron waived privilege as to Dr. Smeland’s views on the broadest reasonable construction of the claim language, understanding of the technology, and materiality (including cumulativeness) of each of the Withheld References.

Regeneron argued that it had fully complied with its disclosure requirements throughout litigation. Merus, on the other hand, pointed to entries on Regeneron’s privilege log that seemed inconsistent with Regeneron’s representations. To resolve this dispute, the district court conducted an in camera review of a subset of the “many thousands” of documents on Regeneron’s log. Regeneron I, 144 F. Supp. 3d at 594. According to the district court, the log turned out to be a “Pandora’s Box.” Id. The district court’s in camera review revealed that there were dozens of “Smeland documents” that were not disclosed during litigation but as to which privilege had now been waived. The district court’s in camera review revealed additional serious discovery issues including a number of relevant non privileged documents that had been withheld on the basis of privilege and documents that should have been produced pursuant to the Order regarding the Jones Memo issue that had not been disclosed.

In all, the district court concluded that there were three categories of documents that presented serious concerns of discovery misconduct:

1. Non-privileged documents that were not produced and instead resided throughout litigation
on the privilege log (e.g., numerous Excel spreadsheets with scientific test results, third party filings to the PTO, and fact statements by non-lawyers not seeking legal advice).
2. Previously privileged documents as to which Regeneron affirmatively waived the privilege by disclosing the “Jones Memo” and that the district court ordered be produced pursuant to its Order.
3. Documents on the privilege log relating to precisely those topics waived by Regeneron when Regeneron filed trial declarations of Drs. Smeland and Jones.

The district court determined that Regeneron’s failure to make full and adequate production of documents in the first two categories during the period of fact discovery independently of the trial misconduct warranted serious sanction. But the third category was the most egregious.  According to the district court, the production failure was undoubtedly larger than the few exemplars revealed by the court’s in camera review. Given the thousands of documents on Regeneron’s privilege log, the district court concluded that it could not possibly learn the full extent of the problem.

As to the first category, there were spreadsheets related to scientific tests, published articles, correspondence with third parties—all of which were relevant to issues in the case and should have been disclosed. Although the ultimate value of the documents in this category was unclear, it was clear that Merus should have received them well before trial.

In the second category, the district court concluded that there were a number of documents on the log involving Dr. Jones discussing his communication with the PTO during prosecution of the ’018 patent. These should have been produced as part of the “Jones Memo” waiver issue.

The third category was most troubling. In the third category, the district court concluded that many documents on the log were directly relevant to the topics as to which privilege has been waived. In particular, these documents were directly relevant to Drs. Smeland and Murphy’s mental impressions of the Withheld References during prosecution of the ’018 patent. The documents would therefore have been relevant to determining if Regeneron specifically intended to deceive the PTO by failing to disclose the Withheld References during prosecution of the ’018 patent.

Based on its review of the privilege log and its in camera review of some of the documents on the log, the district court concluded that Regeneron’s behavior warranted sanctioning. Before imposing its sanction, the district court considered several alternate options including allowing the trial declarations into evidence. To do so, however, the district court would have had to wholesale reopen discovery requiring “a top-to-bottom re-review of the Regeneron privilege log,” “additional document production, fact depositions, and revised expert reports and
depositions.” Regeneron I, 144 F. Supp. 3d at 594–95. Additionally, the district court noted that given its “concerns with Regeneron’s process to date, the [c]ourt would require that any such process only occur with the direct oversight of a special master.” Id. This would have significantly increased the time and cost for both Merus and the district court. As the district court noted, “[a]t this point in the litigation, this is not a fair burden for Merus or this [c]ourt.” Id.

The district court also considered whether striking the trial affidavits and precluding Drs. Smeland and Murphy from testifying at trial would be a sufficient remedy. The court concluded that it would not because doing so would not address the problems caused by the first two categories of undisclosed documents and would not address the delay and disruptions caused by Regeneron’s behavior throughout litigation.

The district court ultimately concluded that it would be unfair to Merus to reopen discovery on the eve of trial and inject further delay in the case entirely due to Regeneron’s behavior. The court also concluded that doing so would impose an unfair burden on the court and require expending substantial additional judicial resources. Further, because Regeneron’s behavior suggested “a pattern” of misconduct, simply reopening discovery, striking the problematic affidavits, and/or shifting costs would not ensure fairness. Id. at 595–96. Accordingly, the district court sought an alternative remedy and concluded that it was appropriate to draw an adverse inference against Regeneron from the undisclosed documents. In particular, the district court concluded that Regeneron failed to disclose the Withheld References to the PTO during prosecution of the ’018 patent with the specific intent to deceive the PTO.


http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/16-1346.Opinion.7-24-2017.1.PDF

Monday, July 24, 2017

Sandoz Files IPR Petition Against Humira Formulation Patent

On July 20, 2017, Sandoz filed an IPR Petition (IPR2017-01824) against Abbvie’s U.S. Patent No. 8,802,100, which covers a stable liquid formulation of Humira.  The ‘100 Patent is similar to Abbvie’s U.S. Patent  8916157, for which the PTAB denied Amgen’s IPR petition:

8,802,100
8916157
(Amgen’s IPR Petition was not instituted)
9085619
(Coherus has filed multiple IPR petitions for this “bufferless patent”)
1. A stable liquid aqueous pharmaceutical formulation comprising
1. A stable liquid aqueous pharmaceutical formulation comprising
1. An aqueous pharmaceutical formulation consisting essentially of:

a) a human IgG1 anti-human Tumor Necrosis Factor alpha (TNF-alpha) antibody, or an antigen-binding portion thereof, at a concentration of 45 to 150 mg/ml,
a) a human IgG1 anti-human Tumor Necrosis Factor alpha (TNF-alpha) antibody, or an antigen-binding portion thereof, at a concentration of 20 to 150 mg/ml,
(a) an anti-tumor necrosis factor alpha antibody comprising a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:3, a CDR2 domain comprising the amino acid sequence of SEQ ID NO:5, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 7, and a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO:4, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 6, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:8, wherein the concentration of the antibody is 50 to 200 mg/ml; and
(b) a polyol,
b) a tonicity agent,
(b) water.
(c) a polysorbate at a concentration of 0.1 to 10 mg/ml, and
(c) a surfactant, and

(d) a buffer system having a pH of 4.5 to 7.0, wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E
(d) a buffer system having a pH of 4.0 to 8.0, wherein the antibody comprises the light chain variable region and the heavy chain variable region of D2E7


Sandoz argues obviousness based on multiple references (over Salfeld in combination with van de Putte, Barrera, Remington and Lam).  According to Sandoz, “a POSA seeking to formulate D2E7 [Humira] would (1) determine the concentration of D2E7 to use based upon AbbVie’s own van de Putte disclosure of clinical data demonstrating the safety and efficacy of 20, 40 and 80 mg doses, which are readily converted to concentrations; (2) use Salfeld’s teaching that D2E7 should be combined with a tonicity agent like mannitol, a surfactant and a buffer; (3) determine the amount of mannitol based upon Remington’s teaching of how to use tonicity agents and AbbVie’s own Barrera disclosure of a D2E7 formulation having 12 mg/ml mannitol; and (4) identify the type and amount of surfactant based on Remington’s teaching that polysorbate is the most widely used surfactant and Lam’s teaching of a 0.01% to about 0.1% concentration of polysorbate, which is readily converted into mg/ml.” 

The PTAB’s denial of Amgen’s petition over a similar patent and Sandoz’s reliance on so many references does not bode well for Sandoz.  


Coherus Drops Two Out of Six IPR Petitions Against Humira Bufferless Patent

Coherus BioSciences, Inc. previously filed six IPR petitions against U.S. Patent No. 9,085,619, which covers a bufferless formulation of Humira.  Coherus has now dropped two of its IPR petitions. Below is the relevant portion of Coherus' motion.

------------------------

Pursuant to the Board’s instruction during the telephone conference held April 6, 2017, Petitioner hereby submits its unopposed motion to dismiss the petitions and terminate proceedings in IPR2017-00826 and IPR2017-00827,  without prejudice, in favor of IPR2017-01009 and IPR2017-01008, respectively.  The petitions in IPR2017-00826 and IPR2017-00827 were filed on January 31, 2017 and notices of accorded filing date were issued on February 24, 2017. 

The Patent Owner has not filed a preliminary response, and the Board has not made any rulings concerning the merits of the petitions.  The Patent Owner has indicated that it does not oppose termination of the IPR2017-00826 and IPR2017-00827 proceedings without prejudice. 

Therefore Petitioner respectfully requests that, pursuant to the Board’s authority under at least 37 C.F.R. §§ 42.5(a) and 42.71(a), Petitioner’s unopposed motion to dismiss and terminate proceeding numbers IPR2017-00826 and IPR2017-00827 without prejudice be granted.


Sandoz Files IPR Petition Against Humira Psoriasis Patent

On July 20, 2017, Sandoz filed an IPR Petition (IPR2017-01824) against Abbvie’s U.S. Patent No.: 9,512,216, which just issued on Dec. 6, 2016.  The ‘216 Patent covers a method of treating chronic plaque psoriasis by administering Humira (adalimumab) starting with an initial dose of 80 mg of adalimumab, followed by 40 mg of adalimumab every other week.  The claims of the ’216 Patent also have a wherein clause requiring that “the patient achieves at least Psoriasis Area and Severity Index (PASI) 75 response at week 12 of the treatment.”


US Patent 9,512,216

1. A method for treating moderate to severe chronic plaque psoriasis,
comprising subcutaneously administering to an adult patient having moderate to severe chronic plaque psoriasis an initial dose of 80 mg of adalimumab, followed by 40 mg of adalimumab every other week starting one week after said first dosing, wherein the patient achieves at least Psoriasis Area and Severity Index (PASI) 75 response at week 12 of the treatment.

Sandoz does not have an anticipatory position.  Rather, Sandoz mainly argues that the claimed method for treating psoriasis is obvious in view of prior art for treating rheumatoid arthritis since the two diseases “are closely related conditions, mediated by TNF-α, that could be treated with the same drugs using the same dosing regimens.”  Sandoz further argues that “it was obvious to administer an 80 mg induction dose of adalimumab one week before beginning the PsO (psoriasis) adalimumab treatment dose because a POSA would have known that (i) an induction dose would provide more rapid relief to patients suffering severe physical and psychological symptoms associated with diseases like PsO; (ii) the first-in-class TNF-α inhibitor infliximab was administered with an induction dose to treat PsO; (iii) an appropriate induction dose for a drug like adalimumab, which has linear (i.e., “first order”) pharmacokinetics and is dosed approximately on its two-week half-life, would be double the 40 mg treatment dose; (iv) 80 mg was shown to be effective in treating RA when dosed weekly;(v) an interval of one week instead of two weeks between administering an induction dose and beginning treatment dosing would have achieved the goal of more rapid relief; and (v) it would be most convenient to use an induction dose (such as 80 mg) that was a multiple of AbbVie’s already approved 40 mg pre-filled syringe.”

Sandoz further argues “that the ‘wherein’ clause of claim 1 merely ‘characterizes the result’ of the claimed method while failing to inform ‘how’ the method is performed, the clause does not limit the scope of the claim.  See Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381 (Fed. Cir. 2003).”  

Sandoz provides the following claim chart in its petition.  Sandoz cites to the ‘216 Patent in the prior art section since the ’216 Patent “demonstrates the result is inherent for some portion of treated patient.”  


Claims 1 and 9
9,512,216
Prior Art
A method for treating moderate to severe chronic plaque psoriasis,

comprising subcutaneously administering
“HUMIRA is supplied in single-use, 1 mL pre-filled syringes, and also 2 mL glass vials as a sterile, preservative-free solution for subcutaneous injection.” 

“The recommended dose of HUMIRA for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.” 
to an adult patient having moderate to severe chronic plaque psoriasis
“[T]reatment was efficacious and safe in PsA and psoriasis.” 

“Adult patients who had moderate to severe plaque psoriasis involving at least 5% of the body surface area and who were in good general health were referred to us . . . or were identified through general advertisements” to participate in the study.  Ex. 1036  at 1843; see also Ex. 1003 at 250, 316.

“Psoriasis . . .  [is an] autoimmune disorder[] in which . . . tumor necrosis factor-alpha . . . has been suggested to play a role.”  Clinical data “suggest[s] . . . treatments that inhibit TNF-alpha may be effective in these disease states.” “HUMIRA . . . works by specifically blocking TNF-alpha.” Abbott sought to “assess safety and efficacy [of adalimumab] in adult patients with moderate to severe chronic-plaque psoriasis.”  Ex. 1052 at 2.

“[I]nfliximab at a dose of 3 mg/kg with methotrexate has proven effective in rheumatoid arthritis.  We therefore aimed to assess the efficacy of infliximab at a dose of 3 mg/kg in combination with methotrexate in the treatment of patients with PsA and skin psoriasis.”  Ex. 1060 at 1.
an initial dose of 80 mg of adalimumab
An induction dose “may be administered initially in order to achieve a peak plasma concentration that lies within the therapeutic range of the drug” and “[t]o reduce the time required for onset of the full therapeutic effect.”  Ex. 1051 at 284-285.

“As a general rule, the loading dose should be twice the size of the maintenance dose if the selected dosage time interval corresponds to the biological half-life of the drug.” Ex. 1051 at 28
followed by 40 mg of adalimumab
“Each syringe delivers 0.8 mL (40 mg) of drug product. . . . Each 0.8 mL HUMIRA contains 40 mg adalimumab . . . .”  Ex. 1026 at 1.
every other week
“The recommended dose of HUMIRA for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.”  Ex. 1026 at 14.
starting one week after said first dosing,
An induction dose “may be administered initially in order to achieve a peak plasma concentration that lies within the therapeutic range of the drug” and “[t]o reduce the time required for onset of the full therapeutic effect.”  Ex. 1051 at 284-285.
[claim 1 only:] wherein the patient achieves at least Psoriasis Area and Severity Index (PASI) 75 response at week 12 of the treatment.
“[A]t Week 12, statistically significantly greater percentages of patients achieved a PASI 75 response or better on D2E7 than those on a placebo treatment.”  Ex. 1001 at 42:5-8  [The ’216 patent is not prior art but its disclosure demonstrates the result is inherent for some portion of treated patient].


Merck, Samsung Accelerate a Biosimilar Price War

Tuesday, July 18, 2017

Federal Circuit: Lyophilized Prodrug Formed by API and Lyophilization Bulking Agent Not Obvious

On July 17, 2017, the Federal Circuit reversed a district court’s decision that Millennium’s U.S. Patent No. 6,713,446 (“the ’446 Patent”) covering the cancer drug Velcade® was obvious.  The district court held that the claims were obvious because they were the inherent result of an allegedly obvious process, viz., lyophilizing bortezomib in the presence of the bulking agent mannitol.  The district court failed to consider that the resulting product was a new chemical entity with superior properties.

The ‘446 Patent claims:

20. The lyophilized compound D-mannitol N-(2- pyrazine)carbonyl-L-phenylalanine-L-leucine boronate.

The inventors of the ‘446 Patent produced a lyophilized formulation using mannitol, a known bulking agent.  The lyophilization resulted in a formulation with improvement in dissolution and stability, which was the results of the formation of a new chemical compound during lyophilization: the claimed ester of bortezomib and mannitol.The mannitol ester of bortezomib acts as a “prodrug,” a compound that converts to or releases the active pharmaceutical ingredient upon administration to a patient.

The district court held that the claims were obvious because they were the inherent result of an allegedly obvious process, viz., lyophilizing bortezomib in the presence of the bulking agent mannitol.  

The Federal Circuit reversed the district court, stating that “the question is whether a person of ordinary skill, seeking to remedy the known instability and insolubility and to produce an efficacious formulation of bortezomib, would obviously produce the D-mannitol ester of bortezomib, a previously unknown compound. The prior art contains no teaching or suggestion of this new compound, or that it would form during lyophilization.  Sandoz identifies no reference or combination of references that shows or suggests a reason to make the claimed compound. No reference teaches or suggests that such a new compound would have the long-sought properties of stability and solubility, and sufficiently dissociate to release bortezomib at an effective rate in the bloodstream, all critical to effective use for treating multiple myeloma. The D-mannitol ester of bortezomib is a new compound with distinct chemical properties. . . .The district court clearly erred in its obviousness analysis. … None of these references, alone or in combination, suggests or teaches that the solution to the problems of creating an efficacious formulation of bortezomib lay in freeze-drying bortezomib with mannitol to form an ester having the necessary properties for stability, storage, and treatment.”

The Federal Circuit also took issue with the district court’s identification of the closest prior art for a showing of unexpected results. “ Millennium presented expert testimony that the lyophilized mannitol ester of bortezomib yielded unexpected results as compared to bortezomib, viz., greatly improved stability, solubility, and dissolution.  However, the district court ruled that bortezomib itself was not the closest prior art, and declined to consider the advantages and benefits of the Velcade® product. The district court’s error stems from its determination that Millennium should have compared the glycerol bortezomib ester, for the Adams Patent included glycerol as one of ten “[p]referred . . . dihydroxy compounds” for “boronate esters.” The bortezomib glycerol ester was not specifically disclosed, prepared, or tested in the Adams Patent. Although Sandoz now argues that the bortezomib glycerol ester is “generically” encompassed by the Adams Patent, Sandoz has not argued that any glycerol ester is specifically disclosed or actually identified in the Adams Patent (or in any other reference).  We conclude that the district court should have treated bortezomib as the closest prior art compound, and acknowledged the unrebutted evidence that the Dmannitol ester of bortezomib exhibited unexpected results compared with bortezomib, including unexpectedly superior stability, solubility, and dissolution.”


Millennium Pharmaceuticals v. Sandoz Inc., July 17, 2017.


Thursday, July 13, 2017

Hospira Files Opposition to Amgen's Motion for a Preliminary Injunction Regarding the Drug Epogen

Below is an excerpt from Hospira's brief (filed on July 6, 2017) in opposition to Amgen's motion for a preliminary injunction regarding Hospira's biosimilar version of the drug Epogen (1:15-cv-00839-RGA).  Hospira argues that it has provided Amgen with an effective notice of commercial marketing as set forth in Supreme Court's Sandoz v. Amgen decision on June 12, 2017.

I. NATURE AND STAGE OF PROCEEDINGS

Hospira is seeking FDA approval to market a biosimilar version of Arngen's Epogen (epoetin alfa) product. Amgen has sued Hospira for infringing two expired patents, U.S. Patent Nos. 5,756,349 (the "'349 Patent") and 5,856,298 (the '"298 Patent"). Amgen also has alleged that Hospira violated the Biologics Price Competition and Innovation Act (the "BPCIA") by failing to provide an effective notice of commercial marketing under 42 U.S.C. § 262(l)(8)(A) of the Act.

The BPCIA provides that a BLA applicant shall provide notice of commercial marketing at least 180 days before the date of first commercial marketing. The United States Supreme Court recently held that this notice can be provided before the applicant has FDA approval. Hospira submitted its abbreviated biologics application ('"BLA") on December 16, 2014 and provided its notice of commercial marketing on April 8, 2015 (the ''Notice" or "Hospira's Notice"). Hospira has thus satisfied section 8(A). Hospira' s proposed biosimilar has not been approved to date by the FDA. Amgen originally filed its Motion for a Preliminary Injunction on May 26, [Redacted]. That position was squarely rejected by the Supreme Court's Sandoz v. Amgen decision on June 12, 2017. Now that the Supreme Court has eviscerated Amgen' s first preliminary injunction argument, Amgen has conjured up a new argument to support its request for an injunction based on arguments that were raised for the first time in the present motion and that contradict the clear factual record and Amgen's prior statements. (D.I. 262.)

II. SUMMARY OF ARGUMENT

The Court should deny Amgen's motion. First, Amgen is unlikely to succeed on the merits. The Supreme Court recently confirmed in Sandoz v. Amgen that a BLA applicant may send a notice of commercial marketing prior to obtaining FDA approval, which Hospira undisputedly did on April 8, 2015. There is no basis in the BPCIA or the Supreme Court's Sandoz opinion for the additional requirements Amgen now asks this Court to impose--none of which were raised in Amgen's initial request for a preliminary injunction.

Hospira provided its Notice in April 2015 and never rescinded or withdrew it. Amgen knows that fact so well that it pointedly complained about it in its Second Amended Complaint filed in October 2016 [Redacted]  Amgen's reliance on one out-of-context quotation from a letter cannot change Hospira's consistent position in correspondence with Amgen and before this Court and Amgen's acknowledgement of that position. Thus, Amgen's first argument that it will succeed on the merits fails.

Amgen's second argument fails because it has no statutory support. The BPCIA does not require Hospira to provide an additional notice of commercial marketing after it receives and responds to a complete response letter (''CRL"). Amgen's argument rehashes the same rationale that the Supreme Court squarely rejected in Sandoz. Indeed, in rejecting Amgen's argument that notice can only be properly provided after FDA approval because that is when the properties of a biosimilar product can be known, the Court explained that '"nothing in §262(1)(8)(A) turns on the precise status or characteristics of the biosimilar application." Sandoz Inc. v. Amgen Inc., No. 15-1039, slip op. at 17 (U.S. June 12, 2017). Thus, Amgen's motion is completely baseless.

Second, Amgen will not suffer any irreparable harm that is cognizable under the BPCIA. Hospira provided a proper Notice more than 180 days ago and can launch its product upon FDA approval. If Amgen loses any sales to Hospira, that is not cognizable "harm"-that is the intended consequence of the BPCIA, which seeks to get competitive biosimilar products into the hands of consumers in a timely fashion. Moreover, Amgen' s argument ignores crucial facts about the marketplace [Redacted] Amgen also suggests that it will face irreparable harm because it may have more patents waiting in the wings. But no such patents were disclosed to Hospira under the BPCIA exchanges, and Amgen has repeatedly told investors that its last material patent on Epogen expired when the '349 patent expired in May 2015.

Third, the balance of equities favors Hospira, not Amgen. Hospira complied with the BPCIA's notice of commercial marketing requirements. Hospira diligently pursued its BLA, including responding to questions from the FDA. As contemplated by the BPCIA, Hospira should now be permitted to launch its product as soon as it obtains approval. Amgen has had patent protection for Epogen since it was launched in 1989, almost thirty years ago. Now, with the only patents that Amgen thought it could assert against Hospira having expired, Amgen improperly is attempting to use the notice of commercial marketing to eke out another six months of market exclusivity, when the Supreme Court has clearly ruled against this. Granting Amgen further exclusivity by issuing an injunction would be improper and inequitable.

Fourth, the public interest does not favor an injunction. The BPCIA created a framework for biosimilar drug product approval with the potential to save billions of dollars in public health costs. The public interest is greatly served by biosimilar drug competition; the public does not benefit from enjoining competitive biosimilars without any factual or legal basis, particularly following a three-decade run of unfettered market exclusivity.

Finally, if an injunction is granted, the Court should require Amgen to post a significant bond, as required by the Federal Rules and Third Circuit case law. However, the Court should address the amount of a bond if and when the scope and timing of an injunction are determined. If the Court were to require Hospira to send a further notice of commercial marketing, it could potentially keep Hospira from launching its product when it obtains FDA approval. That would cause great financial harm to Hospira. In fact, being prevented from launching for even one day after approval would cause unwarranted and significant harm to Hospira [Redacted]-If, at some point, the Court were to decide to issue an injunction, it should allow the parties to present detailed evidence on the bond amount. ID.

[The rest of the brief has been omitted--Please see the actual brief if you want to read further]