Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
1. Claims 1-31 and 33-40 are pending and subject to examination on the merits. Claims 1-20 are withdrawn from consideration as being drawn to non-elected subject matter. Claims 21-31 and 33-40 are currently under examination.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/337,532 filed 02 May 2022.
Withdrawn Objections/Rejections
3. The objection to the specification for having an embedded hyperlink within it is withdrawn, since the hyperlink was deleted from the specification.
4. The objection to the specification for having trademarks without the trademark denotation is withdrawn, since the specification has been amended to include the trademark symbols.
5. The objection to claim 26 for reciting “at from” is withdrawn, since the claim was amended to delete “at.”
6. The objection to claim 27 for reciting “for from” is withdrawn, since the claim was amended to delete “for.”
7. The objection to claim 28 for reciting “at from” is withdrawn, sine the claim was amended to delete “at.”
8. The 35 U.S.C. 112(b) rejection to claim 21 for insufficient antecedent basis is withdrawn, since the claim was amended to recite “a sample” and then subsequently “a stressed sample,” establishing proper antecedent basis.
9. The 35 U.S.C. 112(b) rejection to claim 21 for reciting “reduced lipase activity” without reciting a baseline to which to compare is withdrawn, since the claim was amended to recite “compared to a pharmaceutical composition produced… that was not subjected to stress conditions.”
10. The 35 U.S.C. 112(b) rejection to claim 22 for reciting “said sample” is withdrawn, since claim 22 was amended to delete “said sample.”
11. The 35 U.S.C. 112(b) rejection to claim 29 for reciting “said sample” is withdrawn, since the claim was amended to recited “said stressed sample,” and claim 21 was amended to recite “a stressed sample.”
Maintained/Modified Rejections—necessitated by claim amendments
Claim Rejections - 35 USC § 103
26. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
27. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
28. Claims 21-22, 25, 28, 33, and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al (Graf et al., 2021, Journal of Pharmaceutical Science—cited on the IDS dated 08 January 2026), Lim et al (Lim et al., 2018, Biotechnol. Prog.—cited previously), and FDA (“Quality Review BLA 761055 Dupixent (dupilumab)”, 2017, downloaded 15 April 2026 from < https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761055Orig1s000ChemR.pdf> as a PDF—cited previously) and CSB deepSTABp (cited previously).
Regarding claims 21-22, 25, and 28 and 33, drawn to a method of producing a dupilumab pharmaceutical composition with reduced lipase activity, comprising: (a) subjecting a sample including dupilumab and a lipase to stress conditions to form a sample with inactivated lipase, and (b) formulating said sample with inactivated lipase to produce a dupilumab pharmaceutical composition with reduced lipase activity, wherein said formulating step comprises adding a fatty acid ester to said sample, wherein said fatty acid ester is polysorbate 20 (claim 22), and further, the stress condition is heat (claims 25 and 37) and/or agitation (claim 33), specifically 30-60oC (claim 28), , Graf et al. teaches the identification and characterization of polysorbate-degrading enzymes in a monoclonal antibody formulation (title, abstract), since the degradation of polysorbate by hydrolytically active host cell proteins in drug products may impair the protein-stabilizing properties of polysorbate. Specifically, Graf et al. teaches that CHO cell putative phospholipase B-like 2 (PLBL2) and lysosomal phospholipase A2 (LPLA2) have both been implicated in polysorbate degradation in drug products (p. 3558, column 2, paragraph 1). Graf et al. continues to teach that polysorbate 20 and polysorbate 80 represent the most common class of surfactants in biopharmaceutical formulations and have set the benchmark in terms of protein stabilizing properties, biocompatibility and safety (p. 3558, Introduction, paragraph 1). Additionally, polysorbate degradation was shown to be concomitant with the accumulation of free fatty acids, generally attributed to enzyme-catalyzed hydrolysis from trace amounts of host cell proteins (p.3558, Introduction, column 2, paragraph 2).
Graf et al. does not teach the utilization of a specific stress condition, such as heat shock and/or agitation, to a dupilumab and lipase containing pharmaceutical composition to inactivate or decrease the activity of the lipase. Lim et al. teaches the identification of an endoproteolytic activity endogenous to the Chinese hamster ovary cells, identified as cathepsin D, after the purification of a recombinant therapeutic protein from Chinese hamster ovary cells, leading to the degradation of hydrophobic amino acid residues of the recombinant therapeutic protein after storage as a solution (abstract). Further, the identification of cathepsin D, and its subsequent inactivation by heat inactivation, essentially inactivated the protease, resulting in the production of a stable drug product that had not been possible using column chromatography alone (abstract). Specifically, Lim et al. determined that the protease began to thermally unfold above 45oC, where the Tm was 53oC; therefore, Lim et al. targeted a temperature of 53-55oC for heat inactivation of the protease without affecting the structure of the fusion protein, which had a Tm of 65oC (p. 128, column 1, paragraph 1). Lim et al. achieved thermal heat inactivation of the protease with agitation and reported no detrimental impact on the quality of the fusion protein (p. 128, column 1, paragraph 2).
It is notable that the PLBL2 lipase from Chinese hamster ovary cells (the protein taught above by Graf et al. as implicated in polysorbate degradation) has a calculated Tm of 53oC, which is the same Tm for the protease taught by Lim et al. (See CSB deepSTABp).
Graf et al. and Lim et al. do not teach dupilumab with a lipase. The FDA teaches that dupilumab is produced in CHO cells (p. 45, Introduction, paragraph 1). Additionally, the FDA teaches host cell proteins are found in the formulation of dupilumab (p. 11, CQA: Host Cell Proteins; third entry).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains combine the teachings of Graf et al., Lim et al., and FDA to utilize heat shock as a method to inactivate a lipase contaminant in the dupilumab formulation to inactivate the lipase without the subsequent addition of chemical inhibitors, since Graf et al. teaches that lipases are readily found in Chinese Hamster Ovary (CHO) cell derived monoclonal antibodies (p. 3559, paragraph 1) (and the FDA determined the presence of CHO cell derived host cell proteins in dupilumab formulations), and Lim et al. teaches that heat shock can be utilized to inactivate host cell proteins in protein formulations derived from CHO cells. One would be motivated to combine these teachings to arrive at the instant claims to increase shelf life of monoclonal antibodies, such as dupilumab, with polysorbate as taught by Graf et al. There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Graf et al., Lim et al., and FDA, since Lim et al. teaches the determination of Tm and the subsequent utilization of heat shock to affect the unwanted protein in the formulation without perturbing the protein of interest.
29. Claims 23 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al (Graf et al., 2021, Journal of Pharmaceutical Science—cited on the IDS dated 08 January 2026), Lim et al (Lim et al., 2018, Biotechnol. Prog.—cited previously), and FDA (“Quality Review BLA 761055 Dupixent (dupilumab)”, 2017, downloaded 15 April 2026 from < https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761055Orig1s000ChemR.pdf> as a PDF—cited previously) as applied to claims 21-22, 25, and 28 above, and further in view of Grabarek et al (Grabarek et al., 2020, Journal of Pharmaceutical Sciences—cited previously).
The teachings of Graf et al., Lim et al., and FDA are discussed above and incorporated into the instant rejection. Graf et al., Lim et al., and FDA do not teach polysorbate 80, with oleic acid esters of at least 98%. Grabarek et al. teaches the utilization of polysorbate 80 with an oleic acid ester content of 98%, ChP-PS80, which the Chinese Pharmacopeia (ChP) set more stringent purity requirements for the fatty acid distribution in 2015 (p. 872, column 1, paragraph 2), where this polysorbate 80 with 98% of oleic acid retained its functionality even at 50% hydrolysis testing (p. 879, first column, 3rd paragraph). Additionally, Grabarek et al. teaches that the development of robust formulations consisting of excipients mitigating protein unfolding and aggregation is required to ensure the quality of protein drug products (p. 871, “Introduction,” paragraph 1).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains combine the teachings of Graf et al., Lim et al., and FDA in further view of Grabarek et al. to utilize polysorbate 80 with at least 98% oleic acid content as an excipient to ensure functionality of the polysorbate in a biopharmaceutical to insure functionality even after up to 50% hydrolysis of the polysorbate as taught by Grabarek et al. One would be motivated to combine these teachings to arrive at the instant claims to reduce protein aggregates, which deteriorate product quality and may compromise safety by causing unwanted immune responses as taught by Grabarek et al (p. 871, Introduction, 1st paragraph). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Graf et al., Lim et al., and FDA in further view of Grabarek et al. to utilize polysorbate 80 with 98% oleic acid content as an additive in a biopharmaceutical, since Grabarek et al. teaches the utilization of 98% oleic acid polysorbate 80 in biopharmaceuticals exposed to stress conditions.
30. Claims 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al (Graf et al., 2021, Journal of Pharmaceutical Science—cited on the IDS dated 08 January 2026), Lim et al (Lim et al., 2018, Biotechnol. Prog.—cited previously), and FDA (“Quality Review BLA 761055 Dupixent (dupilumab)”, 2017, downloaded 15 April 2026 from < https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761055Orig1s000ChemR.pdf> as a PDF—cited previously) as applied to claims 21-22, 25, and 28 above, and further in view of Chung et al (Chung et al., 2020, catalysts—cited previously).
The teachings of Graf et al., Lim et al., and FDA are discussed above and incorporated into the instant rejection. Additionally, Graf et al. teaches the release of free fatty acids, lauric acid and myristic acid, over time at a temperature of 30oC under shaking at 200rpm in two batch samples of antibody-1, where the release of free fatty acids is inhibited with the addition of the lipase inhibitor orlistat (p. 3560, Fig. 1; p. 3561, Results and Discussion: Identification of HCPs after enrichment).
However, Graf et al., Lim et al., and FDA do not teach the utilization of agitation from 50-500 rpm for 1-96 hours as a method to inactivate a lipase in a dupilumab containing pharmaceutical. Chung et al. teaches that shaking Lipase A produced on the surface of E. coli decreases the specific activity of the enzyme at speeds over 100 rpm, as a result of shear stress (abstract). Specifically, the 200 rpm shaking rate was utilized for 12 hours (p. 11, “Cultivation Conditions”).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains combine the teachings of Graf et al., Lim et al., and FDA in further view of Chung et al. to utilize agitation, specifically 200 rpm for 12 hours to inactivate a lipase without the subsequent addition of chemical inhibitors, since Graf et al. teaches that lipases are readily found in Chinese Hamster Ovary (CHO) cell derived monoclonal antibodies (and the FDA determined the presence of CHO cell derived host cell proteins in dupilumab formulations), and Chung et al. teaches that agitation can be utilized to inactivate lipases. One would be motivated to combine these teachings to arrive at the instant claims to increase shelf life of monoclonal antibodies, such as dupilumab, with polysorbate as taught by Graf et al. There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Graf et al., Lim et al., and FDA in further view of Chung et al., since Chung et al. teaches shaking/agitation of lipase containing cultures at 200 rpm for 12 hours results in the inactivation of the lipase.
31. Claims 29-31 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al (Graf et al., 2021, Journal of Pharmaceutical Science—cited on the IDS dated 08 January 2026), Lim et al (Lim et al., 2018, Biotechnol. Prog.—cited previously), and FDA (“Quality Review BLA 761055 Dupixent (dupilumab)”, 2017, downloaded 15 April 2026 from < https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761055Orig1s000ChemR.pdf> as a PDF—cited previously) as applied to claims 21-22, 25, and 28 above, and further in view of Gillmeister et al (Gillmeister et al., 2021, US 2021/0163991 A1—cited previously).
The teachings of Graf et al., Lim et al., and FDA are discussed above and incorporated into the instant rejection.
Graf et al., Lim et al., and FDA do not teach the utilization of cation exchange chromatography or size exclusion chromatography to remove high molecular weight species. Gillmeister et al. teaches improved methods for producing recombinant Adeno-Associated Virus particles/proteins by culturing cells in the presence of HDAC inhibitors and increased amounts of sodium salts (abstract). Specifically, the methods pertain to expressing an intact mAb, such as dupilumab (p. 20, column 2, line 16; paragraph 0259). Additionally, Gillmeister et al. teaches isolating the particles via downstream processing such as cation exchange chromatography and size exclusion chromatography (paragraph 0276).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains combine the teachings of Graf et al., Lim et al., and FDA in further view of Gillmeister et al. to utilize cation exchange chromatography and/or size exclusion chromatography to isolate a dupilumab containing particle from adeno-associated virus based vector expressing cells because adeno-associated virus based vectors are the most widely used gene therapy products in development as taught by Gillmeister et al (paragraph 0002). One would be motivated to combine these teachings to arrive at the instant claims to isolate a dupilumab containing biological, since adenovirus associated vectored biologics indicate great potential for delivery in gene therapy indications, as taught by Gillmeister et al (paragraph 0002). There would be reasonable expectation of success, yielding no surprising results when combining the teachings of Graf et al., Lim et al., and FDA in further view of Gillmeister et al. to utilize cation exchange chromatography and/or size exclusion chromatography to isolate a dupilumab containing particle, since Gillmeitster et al. teaches the isolation of dupilumab by the chromatography techniques.
Double Patenting
32. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
33. Claims 21-31 and 33-40 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 13-14 of copending Application No. 18/934,626 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘626 would necessarily anticipate the instant claims.
The instant claims in the broadest are drawn to a method for producing a dupilumab pharmaceutical composition with reduced lipase activity, comprising subjecting a sample including dupilumab and a lipase to stress conditions to form a sample with inactivated lipase; and formulating said sample with inactivated lipase to produce a dupilumab pharmaceutical composition with reduced lipase activity. Dependent claims 22-23 and 32, are drawn to the addition of polysorbate 80. Dependent claims 25-26 are drawn to the stress condition being agitation from 50-500 rpm for 1-96 hours. Dependent claim 28 is drawn to the stress condition being heat stress from 30-60oC. And dependent claims 29-31 are drawn to the utilization of cation exchange and/or size exclusion chromatography to deplete the sample of HMW species. Claims 33-36 are drawn to agitation stress of the sample for 24 or 48 hours at about 250 rpm. And, claims 37-40 are drawn to heat stress of the samples for 0.5 or 1 month at 45oC.
The ‘626 claims are drawn to a method for producing a pharmaceutical composition with reduced lipase activity, comprising subjecting a sample including a protein of interest, wherein said protein of interest is a monoclonal antibody (claim 2), wherein said protein of interest is dupilumab (claim 3), to a stress condition to form a sample with inactivated lipase, subjecting said sample with inactivated lipase to a purification step to from a HMW-depleted sample, and formulating said sample with at least one fatty acid ester, polysorbate 80 (claim 14), wherein the pharmaceutical composition has reduced lipase activity compared to a pharmaceutical composition not subjected to stress conditions, and wherein said reduced lipase activity is measured after a period of storage at long-term storage conditions. Dependent claims 5-6 are drawn to the stress condition being agitation from 50-500 rpm for 1-96 hours. Dependent claims 7-8 is drawn to the stress condition being heat stress from 25-60oC for 2 weeks to 5 years. And dependent claims 9-11 are drawn to purification steps comprising cation exchange and/or size exclusion chromatography.
The difference between the instant claims and the ‘626 claims is that the ‘626 claims recited “wherein said reduced lipase activity is measured after a period of storage at long-term storage conditions” and a time period for the heat stress treatment. However, they would still necessarily anticipate the instant claims, since such measurement could be done in the instant method claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
New Rejections—necessitated by amendments
Claim Rejections - 35 USC § 103
34. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
27. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
35. Claims 34-35 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Graf et al (Graf et al., 2021, Journal of Pharmaceutical Science—cited on the IDS dated 08 January 2026), Lim et al (Lim et al., 2018, Biotechnol. Prog.—cited previously), and FDA (“Quality Review BLA 761055 Dupixent (dupilumab)”, 2017, downloaded 15 April 2026 from < https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/761055Orig1s000ChemR.pdf> as a PDF—cited previously) and CSB deepSTABp (cited previously) as applied to claims 21-22, 25, 28, 33, and 37 above, and further in view of Senanayake and Shahidi (Senanayake and Shahidi, 2002, J. Agric. Food Chem—cited herein).
The teachings of Graf et al., Lim et al., and FDA, and CSB deepSTABp are discussed above and incorporated into the instant rejection.
Graf et al., Lim et al., and FDA, and CSB deepSTABp do not teach shaking a sample at 250rpm (claim 34) for 24hrs (claims 35). Additionally, Graf et al., Lim et al., FDA, and CSB deepSTAB do not teach heat stress at 45oC (claim 38).
Senanayake and Shahidi teach the lipase-catalyzed incorporation of Eicosapentaenoic Acid (EPA) into Borage and Evening Primrose Oils (title). Specifically, Senanayake and Shahidi teach EPA incorporation peaking at 45oC in enzymatic reactions with Pseudomonas sp. lipase preparations with hexane for 24hr with shaking at 250rpm (p. 479; Figs. 1-2).
Therefore, it would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains combine the teachings of Graf et al., Lim et al., and FDA, and CSB deepSTABp with Senanayake and Shahidi to a method for producing pharmaceutical composition with reduced lipase activity, where the composition comprises a dupilumab and a lipase exposed to stressors, including heat and agitation, to enhance enzyme kinetics during the enzymatic reaction. One would be motivated to combine these teachings to arrive at the instant claims to produce structured lipids, such as triacylglycerols with modifications to achieve specific health benefits and/or functional properties, as taught by Senanayake and Shahidi (Introduction, 2nd column, 2nd paragraph). There would be a reasonable expectation of success, yielding no surprising results when combining the teachings of Graf et al., Lim et al., and FDA, and CSB deepSTABp with Senanayake and Shahidi to a method for producing pharmaceutical composition with reduced lipase activity, where the composition comprises a dupilumab and a lipase exposed to stressors, including heat and agitation, since Senanayake and Shahidi teach the exposure of lipases to agitation and heat stressors.
Applicant’s Arguments and Examiner’s Rebuttal:
The applicant traverses the previous obviousness rejection of claims 21-22, 25, and 28 over Graf et al., Lim et al., FDA, and CSB deepSTABp. The applicant also traverses the previous obviousness rejection of claims 23-24 over Graf al., Lim et al., FDA, and CSB deepSTABp and further in view of Grabarek et al. The applicant also traverses the obviousness rejection of claims 26-27 over Graf et al., Lim et al., FDA, and CSB deepSTABp and in further view of Chung et al. Last, the applicant traverses the obviousness rejection of claims 29-31 over Graf et al., Lim et al., FDA, and CSB deepSTABp and in further view of Gillmeister et al. New claims 33-40 were addressed in the above modified and new obvious rejections.
First, the applicant argues that Graf et al does not teach a sample comprising dupilumab and a lipase subjected to stress conditions to inactive the lipase or the composition having excipients. The examiner agrees insofar that the Graf et al. teaching was not utilized to reach these claim limitations. It was used to teach the identification and characterization of polysorbate-degrading enzymes in a monoclonal antibody formulation and also the presence of a host cell lipases, PLBL2 and LPLA2, which are implicated in the degradation of polysorbate in drug products; thus. The Graf et al. teaching demonstrates that a monoclonal antibody formulation may contain a lipase that could be problematic in the formulation and provides motivation to an artisan to inactive its undesirable properties, i.e. the presence of said lipases, and conserving/improving the monoclonal antibody formulation.
Second, the applicant argues that Lim et al. does not mention lipases, stress conditions, or excipients. The examiner agrees insofar that the Lim et al. teaching was not utilized to reach these claim limitations. The Lim et al. teaching was utilized to demonstrate the identification of a problematic host cell protein, the host cell protein’s Tm, and the subsequent utilization of that Tm to apply a thermal stressor to the protein to inactivate it. The linking attribute of the protease taught by Lim et al. and the lipase taught by Graf et al. is that the protease of Lim et al. and the lipase of Graf et al. share the same Tm and thus, thermal inactivation of one would likely translate to the thermal inactivation of the other, providing an artisan with the motivation to combine the teachings.
Third, the applicant argues that CSB deepSTABp and FDA do not cure the deficiencies of Graf and Lam. Specifically, the applicant argues that that the motivation to inactivate a lipase contamination in a dupilumab composition is based on the teachings of FDA, where FDA teaches host cell protein contaminants in dupilumab produced by CHO cells. The applicant argues that the FDA does not call out lipases in its assessment of impurities found as host cell proteins. The examiner agrees insofar that the FDA does not specifically teach lipases as host cell proteins, and the examiner did not rely on FDA to teach the presence of lipases. The examiner relied instead on the teachings of Graf et al., which does explicitly teach the presence of lipases, such as PLBL2, in monoclonal antibody formulations, where said monoclonal antibody is harvested from CHO cells. Therefore, the motivation arises from lipases being a plentiful contaminant in monoclonal antibodies harvested from CHO cells, where Dupilumab is harvested from CHO cells.
Fourth, the applicant argues that Graf et al. does not teach the presence of lipases in monoclonal antibody formulations but rather that the biopharmaceutical formulations have very fast degradation rates. The examiner respectfully disagrees, since Graf et al. teaches:
“The mechanisms of chemically induced instability of PS… have been widely investigated. In particular, the chemical hydrolysis rate for PS has been previously shown to be negiligible under relevant formulation conditions. There fore PS degradation concomitant with the accumulation of free fatty acids, which can give rise to visible and subvisible particles is usually attributed to enzyme-catalyzed hydrolysis of the carboxylic ester bond. Specifically, trace amounts of host cell proteins, a major class of process related impurities generated during the production of biopharmaceuticals, have been previously associated with hydrolytic degradation of PS in the drug product. In this context, lysosomal phospholipase A2 (LPLA2) and putative phospholipase B-like 2 (PLBL2) have been identified in biopharmaceutical formulations affected by PS degradation. CHU et al. demonstrated that PS degradation could be significantly reduced in cell culture harvests by knocking out lipoprotein lipase in CHO host cells.”
Further, the examiner argues that one would have motivation to combine these teachings, since dupilumab is produced in host cells, where lipases are co-precipitated with the desired antibody, leading to the logical combination that inactivating the lipase impurity in the combination would protect the composition, specifically the polysorbate, making the composition more shelf stable and effective as taught above.
Fifth, the applicant continues to argue that Lim et al. is directed to the inactivation of proteases not lipases. The examiner agrees insofar that Lim et al. do utilize thermal inactivation of a protease. However, the linking trait between this teaching and the instant claims, drawn to lipases, is that “the PLBL2 lipase from Chinese hamster ovary cells (the protein taught above by Graf et al. as implicated in polysorbate degradation) has a calculated Tm of 53oC, which is the same Tm for the protease taught by Lim et al. (See CSB deepSTABp). One would be motivated to combine these teachings to arrive at the instant claims to increase shelf life of monoclonal antibodies, such as dupilumab, with polysorbate as taught by Graf et al.
Sixth, the applicant argues that none of the teaching teach heat shock being used to produce a composition with reduced HCP activity. Additionally, the applicant argues that the effect of the inactivation of the protease is prophetic at best. The examiner respectfully disagrees. Lim et al. reports that “the identification and characterization of this protease enabled the development of a robust purification process by implementation of a controlled heat inactivation unit operation that enabled essentially complete inaction od the protease, resulting in the production of a stable drug product” (p. 128, Conclusions). Additionally, since both the instant claims and Lim et al. utilize heat shock, i.e. the same technique/stress, the resultant inactivation of host cell proteins by heat shock is an inherent property of the process. See MPEP 2112.02.
Seventh, the applicant argues that none of the references teach inactivating lipases, as a whole, i.e. not a specific protein of interest. The examiner agrees insofar the teachings focused on a specific example found in the host cell protein co-precipitates to monoclonal antibodies. However, the examiner also contends that heat shock is a universal technique utilized to inactivate many different enzymes. To this end, Tsukidate et al. was motivated by Lim et al. to utilize heat inactivation and then determine the activity of dozens of enzymes found in the antibody containing composition (See Tsukidate, column 1, paragraph 1). Additionally, since this is not an anticipation rejection, one lipase could be representative of a group of lipases outside the findings of surprising results.
Eighth, the applicant argues that the rejection to claims 23 and 24 for the utilization of Grabarek, which does not cure the deficiencies of Graf et al, Lim et al, and FDA. The examiner respectfully disagrees for the reasons stated above. Additionally, the applicant argues the Grabarek et al. utilizes two formulations of polysorbate with out claiming one is better than the other and therefore does not teach a reason to utilize the polysorbate of the instant claim. The MPEP states, "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." (See 2143.01, Section I).
Ninth, the applicant argues that Chung et al. teaches away from the utilization of agitation at high speeds to inactivate a lipase. The examiner respectfully disagrees, since Chung et al teaches, “When the shaking rate was greater than 100 rpm, the specific activity decreased as a result of shear stress” (Abstract).
Tenth, the applicant argues that Gillmeister does not teach or suggest the inclusion of a dupilumab in an AAV and subsequent isolation by chromatography. The examiner respectfully disagrees because Gillmeister does teach that the methods pertain to expressing an intact mAb, such as dupilumab (p. 20, column 2, line 16; paragraph 0259). Additionally, Gillmeister et al. teaches isolating the particles via downstream processing such as cation exchange chromatography and size exclusion chromatography (paragraph 0276). The applicant contends that these are laundry lists of possibilities; however, since this is an obvious type rejection, the list can be expansive and still make the claim obvious.
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
Prosecution Insights