Tuesday, December 18, 2018

Proposed Amendment Bans IPRs for Generics and Biosimilars

https://www.hatch.senate.gov/public/_cache/files/7fda71ea-a175-4a93-9d62-d3bf801a70e9/EHF18270.pdf

https://www.hatch.senate.gov/public/index.cfm/releases?ID=4D895DB2-0F0C-4023-A2AB-7771166AFF00

Senator Orrin Hatch (R-UT), the Chairman of the Senate Republican High-Tech Task Force and co-author of the Hatch-Waxman Act, delivered the following remarks at the Senate Judiciary Committee hearing.  
Thank you, Mr. Chairman. I appreciate your efforts on this bill. As the co-author of Hatch-Waxman, I have a keen interest in ensuring that we have a well-functioning generic drug industry. For that to happen, generics need to be able to obtain access to samples so they can conduct the tests and research necessary to achieve bioequivalency. 
The CREATES Act has a laudable goal. But I don’t believe it strikes the right balance as currently written, and so I will be voting no today. In particular, I believe the damages cap in the bill far exceeds what is necessary to ensure adequate deterrence and could incentivize non-meritorious litigation.
I’d also like to take a moment to discuss the amendment I circulated. I’ve titled this amendment the Hatch-Waxman Integrity Act. 
I mentioned earlier that as the co-author of Hatch-Waxman, I have a keen interest in ensuring we have a well-functioning generic drug industry. Well, there are two sides to that coin. One is ensuring that generic companies are able to develop drugs. The other is ensuring that brand companies have sufficient protections in place to recoup their investments. It won’t do to give generics the ability to develop and market low-cost medications if brand companies don’t have the incentive to create those medications in the first place. And so Hatch-Waxman struck a careful balance, one that has endured for decades.
But it’s recently come to my attention that the inter partes review, or IPR, process that this committee created in the America Invents Act, and which I strongly support, is producing unintended consequences in the Hatch-Waxman context.  
IPR is a critical tool for fighting patent trolls and is of particular importance to the tech community. But it also threatens to upend the careful Hatch-Waxman balance by enabling two separate paths to attack a brand patent.  
First is Hatch-Waxman litigation, which contains numerous carefully calibrated requirements affecting timing, market exclusivity, and FDA approval. Second is IPR, which is a much blunter instrument than Hatch-Waxman and which contains none of the important industry-specific balancing features that come into play in Hatch-Waxman litigation.
I want to be clear that I strongly support IPR. But I do not support its use in a way that upends or eviscerates Hatch-Waxman.
And so I’ve circulated an amendment that would force a party that wishes to challenge a brand patent to choose: the party can file a Hatch-Waxman suit, which carries the benefits of being able to rely on the brand company’s safety and efficacy studies for FDA approval, or it can file an IPR proceeding, which is cheaper, faster, and easier to win. But it can’t do both.
My amendment would preserve Hatch-Waxman as the standard path for generic companies to challenge brand patents, while keeping IPR as an option in situations where other interests come into play. But it would prevent companies from using IPR to put added litigation pressure on innovators above and beyond what Hatch-Waxman already provides. And it would prevent a company that rightfully loses a Hatch-Waxman suit from getting a second bite at the apple. 
I would note as well that for purposes of symmetry, the amendment also applies to post-grant review and to biologics. It will not have any impact on the use of IPR by the tech community.
I won’t be offering my amendment today because it goes beyond the scope of CREATES. But I wanted to discuss it today because it touches on issues that tie back directly to the purpose of CREATES and because it will be a top priority for me during my remaining months in office.

Wednesday, August 15, 2018

Gilead AIDS Patent Question Before the Supreme Court

In the context of patent cases involving pharmaceutical products, does the “actual controversy” requirement of the Declaratory Judgment Act, 28 U.S.C. § 2201(a), require a party seeking to introduce a generic drug product to file an application for FDA approval of that generic drug product before it can file suit for declaratory relief for patent invalidity?

https://www.aidshealth.org/wp-content/uploads/2018/08/36429-cert-petition.pdf

Monday, July 30, 2018

REMICADE CELL CULTURE PATENT NOT INFRINGED SINCE THE SCOPE OF EQUIVALENTS COVERS THE PRIOR ART

Janssen Biotech, Inc. ("Janssen") alleged that the  Defendants Celltrion Healthcare Co. and Celltrion, Inc. (collectively, "Celltrion") and Hospira, Inc. ("Hospira"),  infringed U.S. Patent No. 7,598,083 (the "'083 patent"), under the doctrine of equivalents, by producing a biosimilar infliximab drug (Remicade biosimilar).  The '083 patent claims "a soluble composition, suitable for producing a final volume of cell culture media" with the following ingredients:

anhydrous CaCl2, 5-200 mg;
anhydrous MgCl2, 15-50 mg;
anhydrous MgSO4, 20-80 mg;
FeSO4.7H2O, 0.05-0.50 mg;
Fe(NO3)3.9H2O, 0.01-0.08 mg;
ZnSO4.7H2O, 0.40-1.20 mg;
ferric ammonium citrate, 0.04-200 mg;
KCl, 280-500 mg;
NaCl, 5000-7500 mg;
NaH2PO4.H2O, 30-100 mg;
Na2HPO4, 30-100 mg;
CuSO4.5H2O, 0.001-0.005 mg;
CoCl2.6H2O, 0.001-0.10 mg;
(NH4)6Mo7O24 4H2O, 0.001-0.005 mg;
MnSO4.H2O, 0.000070-0.0080 mg;
NiSO4.6H2O, 0.000025-0.0005 mg;
Na2SeO3, 0.004-0.07 mg;
Na2SiO3.9H2O, 0.02-0.4 mg;
SnCl2.2H2O, 0.000025-0.0005 mg;
NH4VO3, 0.0001-0.0025 mg;
D-Glucose, 500-8000 mg;
sodium pyruvate, 0.0-1000 mg;
sodium hypoxanthine, 0.0-20.0 mg;
glycine, 0.0-150 mg;
L-alanine, 0.0-150 mg;
L-arginine.HCl, 200-5000 mg;
L-asparagine.H2O, 40-250 mg;
L-aspartic acid, 20-1000 mg;
L-cysteine.HCl H2O, 25.0-250 mg;
L-cystine.2HCl, 15-150 mg;
L-glutamic acid, 0-1000 mg;
L-histidine.HCl.H2O, 100-500 mg;
L-isoleucine, 50-1000 mg;
L-leucine, 50-1000 mg;
L-lysine.HCl, 100-1000 mg;
L-methionine, 50-500 mg;
L-ornithine.HCl, 0-100 mg;
L-phenylalanine, 25-1000 mg;
L-proline, 0-1000 mg;
L-serine, 50-500 mg;
L-taurine, 0-1000 mg;
L-threonine, 50-600 mg;
L-tryptophan, 2-500 mg;
L-tyrosine.2Na.2H2O, 25-250 mg;
L-valine, 100-1000 mg;
d-biotin, 0.04-1.0 mg;
D-calcium pantothenate, 0.1-5.0 mg;
choline chloride, 1-100 mg;
folic acid, 1-10 mg;
i-Inositol, 10-1000 mg;
nicotinamide, 0.5-30 mg;
p-aminobenzoic acid, 0.1-20 mg;
riboflavin, 0.05-5.0 mg;
thiamine.HCl, 0.5-20 mg;
thymidine, 0-3.0 mg;
vitamin B12, 0.05-5.0 mg;
linoleic acid, 0.01-2.0 mg;
DL-α-lipoic acid, 0.03-1.0 mg;
pyridoxine.HCl, 0.5-30 mg;
putrescine.2HCl, 0.025-0.25 mg; and
ethanolamine.HCl, 2-100 mg.

The defendants moved for summary judgment of non-infringement on the grounds that Janssen's asserted scope of equivalents would ensnare the prior art. The ensnarement defense prevents the patentee from obtaining, under the doctrine of equivalents, coverage which he could not lawfully have obtained from the PTO by literal claims.

The court conducted a "hypothetical claim" analysis. The hypothetical claim analysis is a two-step process. First, the patentee must "construct a hypothetical claim that literally covers the accused device," which involves expanding the claim limitations to encompass the features of the
accused product.  Second, "prior art introduced by the accused infringer is assessed to determine whether the patentee has carried its burden of persuading the court that the hypothetical claim is patentable over the prior art."

Celltrion did not assert that the hypothetical claims would have been anticipated, but only that they would have been obvious.  In performing an obviousness analysis, the court refused to do a lead compound analysis: “The Federal Circuit's statement that ‘[a] lead compound analysis is not required in analyzing obviousness of a chemical compound when, in the inventing process, there was no lead compound’ does not mean that the lead compound analysis is required whenever evidence shows an inventor or POSA would begin development with a particular composition or product.”

The first prior art relied on by the defendants disclosed a medium with 50 of 52 ingredients required by the hypothetical claims, and for those 50 shared ingredients, the concentration ranges disclosed in the reference partially overlap with the concentration ranges in the hypothetical claims. Similarly, the second reference relied on by the defendants combined 47 of 52 ingredients required by the hypothetical claims, and for those 47 shared ingredients, 46 had partially overlapping concentration ranges.

The two claimed ingredients missing from the first prior art reference that are required by the hypothetical media are ferric ammonium citrate ("FAC") and ammonium metavanadate.  The five claimed ingredients missing from the second prior art reference were: FAC, ammonium metavanadate, manganese (II) sulfate monohydrate, sodium selenite, and tin(II) chloride dehydrate. With respect to the ingredients required by the hypothetical claims that are not disclosed in the references, it was undisputed that the media disclosed in these references contained alternative, previously-known ingredients that were known to provide the same active components as the claimed ingredients, For example, the first reference did not contain Ferric Ammonium Citrate, but had the alternatives ferric fructose and ferric citrate.

Furthermore, “For those 50 ingredients required in the hypothetical media that were previously disclosed in the first reference medium, all of the concentration ranges of the hypothetical claims overlap at least partially with the concentration ranges listed in the reference.”

Janssen argued that because the prior art discloses amounts of each ingredient that overlap only partially with the claimed concentration ranges, the non-overlapping portions constitute differences between the prior art and the hypothetical media that make the latter nonobvious. The court disagreed, stating that “the Federal Circuit has held in a series of cases that partially overlapping concentration ranges establish a prima facie case of obviousness.”

The court held that the "defendants are entitled to summary judgment of non-infringement of
the '083 patent because Janssen has not produced sufficient evidence to prove that the scope of equivalents would not ensnare the prior art."


 1:17-cv-11008 Janssen Biotech, Inc. v. Celltrion Healthcare Co., Ltd. et al.

Friday, December 15, 2017

Injunctive Remedy Under State Law Not Available in Biosimilar Litigation

The Supreme Court instructed the Federal Circuit to determine whether California law would treat noncompliance with § 262(l)(2)(A) as “unlawful.” If the answer is yes, then the court should proceed to determine whether the BPCIA pre-empts any additional remedy available under state law for an applicant’s failure to comply with § 262(l)(2)(A) (and whether Sandoz has forfeited any preemption defense, see 794 F.3d, at 1360, n. 5). .

Federal Circuit's Holding:

As previously discussed, Amgen seeks through state law to impose penalties on Sandoz unavailable under the BPCIA for failure to comply with § 262(l)(2)(A)’s disclosure requirements. This “conflict in the method of enforcement” between the BPCIA and state law creates “an obstacle to the regulatory system Congress chose.” Arizona, 567 U.S. at 406. We must assume that Congress acted intentionally when it did not provide an injunctive remedy for breach of § 262(l)(2)(A)’s disclosure requirements. See Sandoz, 137 S. Ct. at 1675. Where, as here, “Congress made a deliberate choice not to impose” certain penalties for noncompliance with federal law, state laws imposing those penalties “would interfere with the careful balance struck by Congress.” Arizona, 567 U.S. at 405– 06.

Amgen’s reliance on Rodime is misplaced. In Rodime, we determined that the patent laws did not preempt patentee’s state law claims for tortious interference with prospective economic advantage and unfair competition based on the accused infringer’s alleged efforts to dissuade other companies from taking a license to the asserted patent. 174 F.3d at 1306. Our statement, applied to the facts of Rodime, that “[t]he patent laws will not preempt such claims if they include additional elements not found in the federal patent law cause of action and if they are not an impermissible attempt to offer patent-like protection to subject matter addressed by federal law,” id., does not immunize state law claims in other types of cases from ordinary principles of preemption. As discussed supra, the preemption analysis here demonstrates that Amgen’s state law claims conflict with the BPCIA and intrude upon a field, biosimilar patent litigation, that Congress reserved for the federal government.

Monday, November 13, 2017

Genentech's AVASTIN Patents Asserted Against Amgen

On October 10, 2017, Genentech filed a complaint against Amgen alleging that Amgen's biosimilar version of AVASTIN infringes the following patents.

Nitin Balodi of GreyB services helped with the below summary of the patents.


Patent  First Claim
US6054297A 1. A method for making a humanized antibody comprising non-human, import Complementarity Determining Region (CDR) amino acid residues and human Framework Region (FR) amino acid residues, comprising the steps of:
    * (a) obtaining the amino acid sequences of an import variable domain and of a VH subgroup III consensus human variable domain;
    * (b) identifying CDR amino acid sequences in the import and the human variable domain sequences;
    * (c) substituting import CDRs for the corresponding human CDRs;
    * (d) aligning the amino acid sequences of a FR of the import antibody and the corresponding FR of the consensus variable domain;
    * (e) identifying import antibody FR residues in the aligned FR sequences that are non-homologous to the corresponding consensus variable domain residues;
    * (f) determining if the non-homologous import amino acid residue is expected to have at least one of the following effects:
    * (1) non-covalently binds antigen directly;
    * (2) interacts with a CDR; or
    * (3) participates in the VL -VH interface;
    * (g) for any non-homologous import antibody amino acid residue which is expected to have at least one of these effects, substituting that residue for the corresponding amino acid residue in the consensus variable domain FR sequence; and
    * (h) preparing a humanized antibody which binds antigen, wherein the humanized antibody comprises an amino acid sequence determined according to the above steps.
US6121428A 1. A method for recovering a polypeptide comprising:
    * (a) exposing a composition comprising a polypeptide to a reagent which binds to, or modifies, the polypeptide, wherein the reagent is immobilized on a solid phase; and then
    * (b) passing an effluent comprising the polypeptide eluted from or modified by the immobilized reagent, and any reagent leached from the solid phase, through a filter beating a charge which is opposite to the charge of the reagent in and at the pH of, the composition, so as to remove leached reagent from the effluent.
US6242177B1 1. A method of optimizing secretion of a heterologous polypeptide of interest in a cell comprising comparing the levels of expression of the polypeptide under control of a set of nucleic acid variants of a translation initiation region, wherein the set of variants represents a range of translational strengths, and determining the optimal translational strength for production of mature polypeptide, wherein the optimal translational strength is less than the translational strength of the wild-type translation initiation region.
US6331415B1 1. A process for producing an immunoglobulin molecule or an immunologically functional immunoglobulin fragment comprising at least the variable domains of the immunoglobulin heavy and light chains, in a single host cell, comprising the steps of:
(i) transforming said single host cell with a first DNA sequence encoding at least the variable domain of the immunoglobulin heavy chain and a second DNA sequence encoding at least the variable domain of the immunoglobulin light chain, and
(ii) independently expressing said first DNA sequence and said second DNA sequence so that said immunoglobulin heavy and light chains are produced as separate molecules in said transformed single host cell.
US6407213B1 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.
US6417335B1 1. A method for purifying an antibody from a composition comprising the antibody and a contaminant, which method comprises:
(a) loading the composition onto a cation exchange resin, wherein the amount of antibody loaded onto the cation exchange resin is from about 20 mg to about 35 mg of the antibody per mL of cation exchange resin; and
(b) eluting the antibody from the cation exchange resin.
US6586206B1 1. A method of making recombinant proteins using one or more apoptosis inhibitors, comprising the steps of:
(a) providing a vector comprising a gene encoding caspase-9 dominant negative protein,
(b) providing a vector comprising a gene encoding a protein of interest,
(c) providing a Chinese hamster ovary (CHO) host cell,
(d) transforming or transfecting the host cell with the vector of steps (a) and (b),
(e) providing cell culture media,
(f) culturing the transformed or transfected host cell in the cell culture media under conditions sufficient for expression of the protein of interest and the caspase-9 dominant negative protein, and optionally
(g) recovering or purifying the protein of interest from the host cell and/or the cell culture media.
US6620918B2 1. A method for purifying polypeptide monomers from a mixture consisting essentially of said polypeptide monomers, and dimers or multimers of said polypeptide monomers or both dimers and multimers of said polypeptide monomers, wherein the method consists essentially of applying the mixture to a cation-exchange or anion-exchange chromatography resin in a buffer, wherein if the resin is cation-exchange, the pH of the buffer is about 4-7, and wherein if the resin is anion-exchange, the pH of the buffer is about 6-9, and eluting the mixture at a gradient of about 0-1 M of an elution salt, wherein the monomer is purified from the dimers or multimers or both present in the mixture, and wherein the purified monomer has a purity of greater than 99.5% and the monomer yield is greater than 90%.
US6870034B2 1. A method for purifying a protein, which comprises a C H2/C H3 region, from a contaminated solution thereof by Protein A chromatography comprising:
(a) adsorbing the protein from said contaminated solution to Protein A immobilized on a solid phase;
(b) removing contaminants by washing the solid phase with a composition comprising detergent and salt at about pH 4.5 to about 5.5; and
(c) recovering the protein from the solid phase with an elution buffer having a pH in the range from about 2 to about 5.
US6884879B1 1. Isolated nucleic acid encoding a humanized variant of a parent anti-VEGF antibody which parent antibody comprises non-human variable domains, wherein said humanized variant binds human VEGF and comprises the following heavy chain Complementary Determining Region (CDR) amino acid sequences: SEQ ID NO:128 as CDRH1, SEQ ID NO:2 as CDRH2 and SEQ ID NO:129 as CDRH3.
US7060269B1 1. A method for inhibiting VEGF-induced angiogenesis in a subject, comprising administering to said subject an effective amount of a humanized anti-VEGF antibody which binds human VEGF with a Kd  value of no more than about 1×10-8M, said humanized anti-VEGF antibody comprising a heavy chain variable domain sequence of SEQ ID NO:116 and a light chain variable domain sequence of SEQ ID NO:115.
US7169901B2 1. A humanized anti-vascular endothelial growth factor (VEGF) antibody or an antigen binding fragment thereof which binds human VEGF with a Kd value of no more than about 1×10-8M, said humanized anti-VEGF antibody having a heavy a chain variable domain comprising the following heavy chain complementarity determining region (CDR) amino acid sequences: CDRH1 (GYX1FTX2YGMN), wherein X1 is T or D and X2 is N or H; SEQ ID NO:130), CDRH2 (WINTYTGEPTYAADFKR; SEQ ID NO:2) and CDRH3 (YPX1YYGX2SHWYFDV, wherein X1 is Y or H and X2 is S or T; SEQ ID NO:131).
US7375193B2 1. An aqueous formulation useful for inhibiting VEGF-induced angiogenesis in a subject, comprising as the active compound a humanized anti-VEGF antibody in a buffer, wherein the anti-VEGF antibody comprises a heavy chain variable domain comprising the following heavy chain complementarity determining region (CDR) amino acid sequences: CDRH1 (GYTFTNYGMN; SEQ ID NO: 1), CDRH2 (WINTYTGEPTYAADFKR; SEQ ID NO: 2) and CDRH3 (YPHYYGSSHWYFDV; SEQ ID NO: 3) and a light chain variable domain comprising the following light chain CDR amino acid sequences: CDRL1 (SASQDISNYLN; SEQ ID NO: 4), CDRL2 (FTSSLHS; SEQ ID NO: 5) and CDRL3 (QQYSTVPWT; SEQ ID NO: 6).
US7622115B2 1. A method for treating cancer in a patient comprising administering an effective amount of bevacizumab and assessing the patient for gastrointestinal perforation during treatment with bevacizumab.
US7807799B2 1. A method of purifying a protein which comprises a CH2/CH3 region, comprising subjecting a composition comprising said protein to protein A affinity chromatography at a temperature in the range from about 10 ° C. to about 18 ° C.
US7923221B1 1. A method for making an antibody heavy chain or fragment thereof and an antibody light chain or fragment thereof each having specificity for a desired antigen, wherein the heavy chain or fragment thereof comprises a human constant region sequence and a variable region comprising non human mammalian variable region sequences, the method comprising culturing a recombinant host cell comprising DNA encoding the heavy chain or fragment thereof and the light chain or fragment thereof and recovering the heavy chain or fragment thereof and light chain or fragment thereof from the host cell culture.
US8044017B2 1. A method for purifying a polypeptide from a composition comprising the polypeptide and contaminants, which method comprises the sequential steps of:
(a) loading the composition onto an ion exchange resin with an equilibration buffer having a first salt concentration;
(b) washing the ion exchange resin with a wash buffer until a predetermined protein concentration is measured in the flowthrough, wherein the salt concentration of the wash buffer increases from an initial, second salt concentration that is greater than the salt concentration of the equilibration buffer, to a final, third salt concentration;
(c) passing a fixed volume of wash buffer at the final, third salt concentration over the cation exchange resin; and
(d) eluting the polypeptide from the ion exchange resin with elution buffer that has a salt concentration that is greater than the final salt concentration of the wash buffer.
US8460895B2 1. A method for the recombinant production of a polypeptide in a eukaryotic host cell modified in the citrate cycle to express a cytosolic pyruvate carboxylase, the method comprising the following steps:
(a) cultivating the eukaryotic host cell in a suitable medium under conditions which allow the expression of the polypeptide, wherein the content of dissolved CO 2 in the medium is maintained at a constant value in the range of 10% to 20% of the saturated solution of CO2 under a given set of conditions, and wherein a base is added to adjust the pH of the medium; and
(b) recovering the polypeptide from the cell or from the medium.
US8512983B2 1. A process for producing a polypeptide in a mammalian host cell expressing said polypeptide, comprising culturing the mammalian host cell in a production phase of the culture in a glutamine-free production culture medium containing asparagine, wherein the asparagine is added at a concentration in the range of 7.5 mM to 15 mM.
US8574869B2 1. A method for the prevention of the reduction of a disulfide bond in an antibody expressed in a recombinant host cell, comprising, following fermentation, sparging the pre-harvest or harvested culture fluid of said recombinant host cell with air, wherein the amount of dissolved oxygen (dO2) in the pre-harvest or harvested culture fluid is at least 10%.
US8633302B2 1. A method for concentrating an immunoglobulin solution by tangential flow filtration, characterized in that the transmembrane pressure and the cross-flow are variable, and changed during the filtration process according to the concentration of the immunoglobulin to be concentrated, wherein
i) a transmembrane pressure of from 1.4 bar to 1.6 bar and a cross-flow of from 75 ml/min. to 90 ml/min. is applied in a concentration range up to 30 mg immunoglobulin per ml of solution to be concentrated,
ii) a transmembrane pressure of from 0.8 bar to 0.9 bar and a cross-flow of from 140 ml/min. to 160 ml/min. is applied in a concentration range of from 15 mg/ml up to 55 mg/ml, and
iii) a transmembrane pressure of from 0.8 bar to 0.9 bar and a cross-flow of from 120 ml/min. to 140 ml/min is applied in a concentration range of more than 45 mg/ml up to about 130 mg/ml.
US8710196B2 1. A method for purifying an antibody from a composition comprising the antibody and a contaminant, which method comprises the following steps performed sequentially:
(a) binding the antibody to a cation exchange material with an equilibration buffer at a first conductivity;
(b) washing the cation exchange material with a wash buffer, wherein the conductivity of the wash buffer increases from a second conductivity that is higher than the first conductivity to a third conductivity during the washing;
(c) passing a fixed volume of wash buffer at the third conductivity over the cation exchange material; and
(d) eluting the antibody from the cation exchange material with an elution buffer at a fourth conductivity that is higher than the third conductivity.
US9441035B2 1. A method of producing bevacizumab, or a fragment thereof, comprising the step of culturing a Chinese hamster ovary (CHO) cell comprising a nucleic acid encoding bevacizumab or fragment thereof in a cell culture medium, wherein the cell culture medium comprises copper, insulin, and cystine, wherein the cystine is at a concentration of from 1.25 mM to 2.5 mM, and wherein the cell produces bevacizumab, or a fragment thereof.
US9487809B2 1. A method for reducing lactate production in cultured cells, the method comprising culturing cells comprising a first heterologous nucleic acid sequence encoding a small interfering RNA (siRNA) specific for a lactate dehydrogenase (LDH) and a second heterologous nucleic acid sequence encoding an siRNA specific for a pyruvate dehydrogenase kinase (PDHK), wherein the first heterologous nucleic acid sequence is operably linked to a first promoter, and wherein the second heterologous nucleic acid sequence is operably linked to a second promoter, wherein the cultured cells have a polypeptide productivity of at least about 68% higher than cultured cells without the heterologous nucleic acid sequence comprising siRNA specific for PDHK and the siRNA specific for LDH.