Sunday, May 21, 2017

Amgen Sues Coherus over Neulasta with a Single Protein Purification Patent

On May 10, 2017, Amgen sued Coherus over Neulasta with a single patent that covers a method for purifying proteins.  After exchanging list of patents, Amgen and Coherus negotiated under 42 U.S.C. § 262(l)(4) as to “which, if any, patents listed under paragraph (3) by the subsection (k) applicant or the reference product sponsor shall be the subject of an action for patent infringement under paragraph (6).” Amgen and Coherus then agreed that U.S. Patent No. 8,273,707 “would be included in the action for patent infringement under 42 U.S.C. § 262(l)(6).”  Coherus has denied infringement of the ’707 Patent in its detailed statement under 42 U.S.C. § 262(l)(3)(B).

Claim 1 of the ’707 Patent recites:
A process for purifying a protein on a hydrophobic interaction chromatography column such that the dynamic capacity of the column is increased for the protein comprising
mixing a preparation containing the protein with a combination of a first salt and a second salt,
loading the mixture onto a hydrophobic interaction chromatography column, and
eluting the protein,
wherein the first and second salts are selected from the group consisting of citrate and sulfate, citrate and acetate, and sulfate and acetate, respectively, and wherein the concentration of each of the first salt and the second salt in the mixture is between about 0.1 M and about 1.0.


The ‘707 Patent does not cover dosing or a formulation of Neulasta, but is directed to a method for purifying proteins.  Is it possible that Amgen has no other Neulasta patents that Coherus infringes?  We do not know what patents were on the list that Amgen gave to Coherus, but the inclusion of a single protein purification patent in this suit does not bode well for Amgen.

AMGEN V. COHERUS (D. DEL.)

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Wednesday, May 17, 2017

CELLTRION’S HERCEPTIN HUMANIZATION IPRS

On May 8, 2017, Celltrion filed two filed two petitions for inter partes review of Genentech’s U.S. Patent No. 6,407,213, which covers methods for humanizing an antibody by replacing the CDR flanking regions of a mouse antibody with human flanking regions, and then reverting back to the mouse sequence at certain positions in the flanking regions to keep the mouse CDRs in optimal conformation.  Mylan previously filed two IPR petitions (IPR2016-01694 and IPR2016-01693) against the‘213 Patent, but settled with Genentech before the PTAB had a chance to institute an IPR proceeding.

Herceptin is a humanized mouse monoclonal antibody.  Mouse monoclonal antibodies can possess a desirable therapeutic effect, but patients receiving mouse antibodies experience a human anti-mouse antibody (HAMA) immunogenicity response.  To neutralize the HAMA response, the constant region and the variable framework regions flanking the Complementarity Determining Regions (CDRs) are replaced with human sequences, leaving only the CDRs of the mouse.  This extensive humanization, however, has the drawback of changing the conformation of the mouse CDRs, making the antibody less effective.  To maintain the effectiveness of the antibody, Genentech’s patent claims substituting some of the amino acids from the human flanking regions back to the mouse sequence. 

Genentech’s ‘213 Patent claims a “humanized antibody” with amino acid substitution in the Framework Regions (FR) flanking the CDRs:

1. A humanized antibody variable domain comprising non-human Complementarity Determining Region (CDR) amino acid residues which bind an antigen incorporated into a human antibody variable domain, and further comprising a Framework Region (FR) amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, and 92H, utilizing the numbering system set forth in Kabat. 

30. An antibody which binds p185HER2 and comprises a humanized antibody variable domain, wherein the humanized antibody variable domain comprises non-human Complementarity Determining Region (CDR) amino acid residues which bind p185.sup.HER2 incorporated into a human antibody variable domain, and further comprises a Framework Region (FR) amino acid substitution at a site selected from the group consisting of: 4L, 38L, 43L, 44L, 46L, 58L, 62L, 65L, 66L, 67L, 68L, 69L, 73L, 85L, 98L, 2H, 4H, 36H, 39H, 43H, 45H, 69H, 70H, 74H, 75H, 76H, 78H and 92H, utilizing the numbering system set forth in Kabat

60. The antibody of claim 30 wherein the residue at site 78H has been substituted.

Claims 30 and 60 specify that the antibody is an antibody that binds to p185HER2, which is the target for Genentech’s Herceptin.  These claims also have a substitution at 78H (absent in claim 1), which both Mylan and Celltrion admit is present in Herceptin.  Celltrion’s position is that the prior art teaches the claimed substitution, including the substitution at residue 78H.  Below are relevant excerpts from Celltrion’s IPR petitions. 
--------------
Queen 1990 [WO 1990/07861] thus provided a detailed rationale for substituting particular amino acids, and how to do it in a detailed and objective way. Queen 1990 explicitly instructed a POSA to look to the “Brookhaven Protein Data Bank” (i.e., the PDB database) to identify the framework residues that: “could interact with the CDR atoms” (Criterion IV; Ex. 1050 at 14:21–25); were conserved (Criterion II; or were adjacent to CDRs (Criterion III). Ex. 1003 at ¶¶120–26, 259–60. A POSA following this roadmap would have quickly determined that 19 light (L) chain ((4L, 58L, 62L, 66L, 67L, 73L, 85L and 105L (CDR contact residues) and 23L, 25L, 33L, 35L, 49L, 53L, 57L, 88L, 90L, 97L, 98L) (Kabat and Chothia adjacent residues)) and 23 heavy (H) chain residues (2H, 24H, 39H, 45H, 69H, 71H, 73H, 76H, 78H, 93H and 103H) (CDR contact residues) and 25H, 30H, 33H, 36H, 49H, 52H, 56H, 66H, 94H, 95H, 102H and 103H (Kabat and Chothia adjacent residues)), including claim 1 positions 4L, 58L, 66L, 67L, 69L, 73L, 2H, 36H, 45H and 69H, as well as adjacent residues 98L and 36H, meet these requirements.
----------------
The substitutability of residues 71H, 73H, 78H and 93H would not have been surprising or unexpected. The importance of heavy chain residue 71H was well-known by those in the field, including patentees. See Ex. 1001 at 3:1–8 (recognizing framework residues that “critically affect[] the conformation of particular CDRs and thus their contribution to antigen binding,” citing to Tramontano. Dr. Riechmann also cites to antibody 4–4–20 (4Fab), having a cluster of close contacts (less than 3Å) at 73H, 78H and 93H, which “emphasizes the relative importance of these contacts made . . . in maintaining antibody conformation.”
-----------------

The PTAB has not yet made a decision on the IPR petitions.  

Monday, May 15, 2017

Genentech Shuts Down All Cabilly IPRs

Genentech's Cabilly Patent, U.S. Patent No. 6331415, covers production of antibodies by producing both the light and the heavy chain of an antibody in a single host cell.  The Cabilly patent is highly valuable to Genentech since it covers the main method by which antibodies are produced.

Genentech has shut down all IPRs against the Cabilly patent by settling with all petitioners whose IPR petitions were granted.  Genentech settled before the PTAB made a decision on the merits.

AIA Review #
Filing Date
Institution Decision Date
Petitioner
PO/Respondent Patent #
PO/Respondent
Status


Blog Notes
IPR2015-01624
07/27/2015
02/05/2016
Sanofi-Aventis U.S. LLC
6331415
Genentech, Inc.
Terminated
Genentech settled after the institution of the IPR. 
IPR2016-00383
12/30/2015
06/23/2016
GENZYME CORPORATION
6331415
Genentech Inc.
Terminated
The IPR petition was denied.
IPR2016-00460
01/15/2016
06/08/2016
Genzyme Corporation
6331415
GENENTECH, INC.
Terminated
Genentech settled after the institution of the IPR. 
IPR2016-00710
03/03/2016
09/08/2016
Mylan Pharmaceuticals Inc.
6331415
Genentech, Inc.
Terminated
Genentech settled after the institution of the IPR. 
IPR2016-01373
07/07/2016
01/03/2017
Merck Sharp & Dohme Corp.
6331415
Genentech, Inc.
Institution Denied
The IPR petition was denied.
IPR2017-00047
10/11/2016
01/03/2017
Merck Sharp & Dohme Corp.
6331415
Genentech, Inc.
Terminated
Genentech settled after the institution of the IPR. 

Other players in this filed, such as Celltrion, Amgen, or Pfizer, may now have no choice but to file an IPR petition against the Cabilly patent.   

Pfizer Files IPR Petitions Against Biogen’s Rituximab Patents

On April 21, 2017, Pfizer filed two IPR petitions against Biogen’s patents directed to methods of treating non-Hodgkin’s Lymphoma with rituximab:

Patent Number/IPR
Claim 1
8,557,244
IPR2017-01166
1. A method of treating a patient with diffuse large cell lymphoma, comprising administering an unlabeled chimeric anti-CD20 antibody and CHOP (cyclophosphamide, hydroxydaunorubicin/doxorubicin, vincristine, and prednisone/prednisolone) chemotherapy to the patient, wherein the patient is >60 years old and has bulky disease (tumor >10 cm in diameter).
8,329,172
IPR2017-01167
1. A method of treating low grade B-cell non-Hodgkin's lymphoma in a human patient comprising administering to the patient chemotherapy consisting of CVP therapy to which the patient responds, followed by rituximab maintenance therapy, wherein the maintenance therapy comprises four weekly administrations of rituximab at a dose of 375 mg/m.2 every 6 months, and wherein the maintenance therapy is provided for 2 years.
9,296,821
IPR2017-01095

Filed by Celltrion but not Pfizer
1. A method for treating low grade or follicular non-Hodgkin's lymphoma (NHL) comprising administering to a patient a therapeutically effective amount of rituximab during a chemotherapeutic regimen, wherein the chemotherapeutic regimen consists of cyclophosphamide, vincristine, and prednisone (CVP therapy), wherein the method comprises administering 375 mg/m2 of rituximab, and wherein the method provides a beneficial synergistic effect in the patient.

Celltrion and Boehringer have also filed petitions against these two patents:

AIA Review #
Filing Date
Institution Decision Date
Petitioner
PO/Respondent Patent #
Respondent
Status
IPR2015-00418
12/15/2014
07/13/2015
Boehringer Ingelheim Pharmaceuticals, Inc.
8329172
Biogen Inc.
Terminated
IPR2017-01093
03/15/2017
Celltrion Inc.
8329172
Biogen, Inc.
Pending
IPR2017-01166
04/21/2017
Pfizer, Inc.
8329172
Pending







IPR2017-01094
03/15/2017

Celltrion Inc.
8557244
Biogen, Inc.
Pending
IPR2017-01167
04/27/2017

Pfizer, Inc.
8557244

Pending

The PTAB denied Boehringer’s IPR petition because Boehringer failed to show that the prior art it relied on (clinical trials) were publicly available before the priority date of the patents.  Celltrion subsequently filed petitions against the same patent relying on the same clinical trials as Boehringer.  Celltrion, however, relied on a new declarant who allegedly has personal knowledge of the clinical trials and could verify that the clinical trials were publicly disclosed before the priority dates of the patents. 

In its IPR petitions, Pfizer does not rely on the clinical trials relied on by Boehringer and Celltrion.  Pfizer relies on the following two grounds of invalidity, which include the Coiffier and the McNeil references that were also relied on by Celltrion:

Ground 1
[A] POSA would have been motivated to add rituximab to a regimen of CHOP for patients over 60 with bulky disease, particularly in light of Shipp’s[1] teaching that CHOP treats patients over 60 years old with bulky disease and Link’s[2] teaching that the addition of rituximab adds efficacy but not toxicity. McNeil[3] expressly suggested combining these teachings by suggesting “CHOP plus the monoclonal antibody [rituximab]” as an “alternative” for patients over 60 years old with intermediate-grade NHL.

Ground 2
A POSA would have been motivated to combine rituximab, a “chimeric antiCD20 antibody,” to the regimen disclosed by Shipp in light of Coiffier.[4] Coiffier taught that rituximab—a chimeric anti-CD20 antibody—had activity in intermediate grades of NHL, but without the toxicity of normal CHOP regimens. Coiffier demonstrated that although one of the “dominant features of [its patient] population [was] a relatively old age,” the response rate was “above the minimal desirable threshold that was defined by the protocol and is similar to what would be expected with single-agent therapy in this patient population.” A POSA would have understood from Coiffier that rituximab had anti-cancerous activity in elderly patients with NHL and was a viable treatment option for them.



[1] J. Clin. Oncol., 13(12):2916-2923 (1995)
[2] American Society of Clinical Oncology, Program/Proceedings, Thirty-Fourth Annual Meeting, (May 1998)
[3] J. Nat’l Cancer Inst., 90(4):266-67
[4] Blood, 92(6):1927-1932 (1998)

Sunday, May 7, 2017

Patent Tip of the Day

A design patent application cannot claim benefit of a provisional utility patent application. It is important to let clients know at the time of filing of a provisional application that they cannot later file a design application that claims the benefit of the provisional application. A non-provisional utility patent application, however, can claim benefit of a design application, and vice versa. If a utility application is rejected and the client desperately needs a patent, always look at the possibility of filing a design application by claiming benefit of the non-provisional utility application. Make sure that the drawings of the design application are supported by the non-provisional application so that the claim of priority is valid.

Wednesday, May 3, 2017

Federal Circuit: “Batches Limitation” Requires a Process that Achieves Consistency Between Batches of Bivalirudin (Angiomax)

The Medicines Company brought a suit against Mylan for submitting an ANDA for the drug bivalirudin (Angiomax).  The Medicines Company asserted the following two patents against Mylan: 

7,582,727
Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6% as measured by HPLC.
7,598,343
1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier, for use as an anticoagulant in a subject in need thereof, said batches prepared by a compounding process comprising: (i) dissolving bivalirudin in a solvent to form a first solution; (ii) efficiently mixing a pH-adjusting solution with the first solution to form a second solution, wherein the pH-adjusting solution comprises a pH-adjusting solution solvent; and (iii) removing the solvent and pH-adjusting solution solvent from the second solution; wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6% as measured by HPLC. 

The inventors of these two patents realized that during mixing, certain “hot spots” occurred that increased the impurity level of Asp9-bivalirudin, an undesired impurity.  The inventors developed an improved, “efficient mixing” process for mixing the pH-adjusting solution with the bivalirudin solution that minimized the formation of these hotspots. This improved “efficient mixing” process resulted in batches that consistently satisfied the FDA’s 1.5 percent limit on the level of Asp9- bivalirudin. Moreover, the Asp9 level of batches compounded using the improved “efficient mixing”process never exceeded 0.6 percent.

The district court held on summary judgment that the asserted claims of the ’343 patent were not infringed because Mylan did not satisfy the “efficient mixing” limitation of those claims. After conducting a bench trial, the court held that the asserted claims of the ’727 patent were infringed because those claims did not include an “efficient mixing” limitation. The Federal Circuit held that both the ’727 and ’343 patents include a “batches” limitation that requires batch consistency, which, according to the patents in suit, is achieved through efficient mixing:

The batches limitation restricts the claims of the ’727 patent (as well as the ’343 patent) to “batches hav[ing] a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%.” At the outset, we note that the batches limitation cannot be literally construed to cover individual batches of base-compounded bivalirudin having Asp9 levels that “do[] not exceed about 0.6%.” Such a construction would render the claims of the ’727 patent invalid in light of Medicines’ numerous pre-critical-date sales of ANGIOMAX batches having Asp9 levels below 0.6 percent. See Medicines, 72 F. Supp. 3d at 864. Rather, properly construed, what the batches limitation requires is the use of a process that achieves batch consistency. This requirement follows from simply reading the batches limitation against the specification’s definition of the term “batches,” as slightly revised by the district court with the agreement of the parties to clarify that the “batches” must be made by a particular compounding process. See Medicines, 2012 WL 3234282, at *5. That definition limits the “batches” claimed by the patents in suit to either “all batches prepared by a same compounding process,” or “a single batch . . . wherein the levels of [Asp9-bivalirudin] represent levels for all potential batches made by said process.” ’727 patent, col. 5 ll. 24–36 (emphasis added); ’343 patent, col. 5 ll. 24–36. The batches limitation therefore requires a process that achieves consistency between batches produced from the “same compounding process”—i.e., batch consistency.
The Federal Circuit limited the batch claims by the process of making the batches despite the ‘727 Patent lacking the process limitation of “efficient mixing.”

The Medicines Company v. Mylan, Inc. (Fed Cir. April 6, 2017).
http://www.cafc.uscourts.gov/sites/default/files/opinions-orders/15-1113.Opinion.4-4-2017.1.PDF