Detailed Action
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 .
Claims 1, 12-22, 25-30, 32, 34-35, and 68-69 are pending.
Claims 2-11, 23-24, 31, 33, and 36-67 are cancelled.
Claims 13-18, 35, and 68-69 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected groups/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/27/2024.
Claim 25 is amended.
Claims 1, 12, 19-22, 25-30, 32, and 34 are under examination on the merits.
Withdrawn Claim Rejections
The rejection of claim 25 under 35 USC §112(b) is withdrawn as addressed by the clarifying claim amendments dated 02/27/2026.
Claim Rejections
Claim Rejections - 35 USC § 112
Mainained-35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 26 remains rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 26 recites the broad recitation “wherein the oxidation is reduced by 40%”, and the claim also recites that the oxidation is reduced by “50%, 75%, 80%, 85%, 90%, 95%, or 99%”, which is the narrower statement of the range/limitation. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such various alternatives is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claim.
Maintained-Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 21-22, 25-30, 32, and 34 is/are rejected under 35 U.S.C. 103 as being obvious over ‘Genentech’ (WO 2017/117304 A1; IDS dated 05/19/2021) in view of Yu et al (J Pharm Sci. 1984 Jan;73(1):82-6; doi: 10.1002/jps.2600730122) and Alavattam et al (US 2014/0314778 A1; IDS dated 05/19/2021).
Regarding claims 1 and 34, Genentech teaches a method of reducing oxidation of a polypeptide in an aqueous formulation (and a kit comprising the liquid formulation, see for example, paragraphs 0019 and 0029 at pages 6 and 8 bridging 9) comprising adding an amount of N-acetyltryptophan (NAT) to the formulation (see for example, page 4 at paragraph 8), at a concentration of 0.1-5 mM (see for example, page 4 at paragraph 9), wherein the oxidation of the polypeptide is reduced by 50-99% (see for example, page 4 at paragraph 10). The formulation comprises protein (which may be an antibody (see for example, page 2 at paragraph 0003 and claim 14 at page 126)) wherein addition of NAT to formulations has resulted in reduction of methionine residue oxidation in proteins and peptides (see for example, claim 1 and paragraphs 0003-0004 and 0008 at pages 1-2, 4, 125); further note that formulations comprising 0.3 mM NAT and 5mM L-Met or 1.0 mM NAT and 5 mM L-Met have been taught and suggested as formulations to test and to use to reduce oxidation/oxidative stress (see for example, paragraphs 0107, 0326 and 0328-0329 [teaching an upper limit of 20mM L-Met] at pages 32, 115-116). In some embodiments, the formulation is a pharmaceutical formulation suitable for administration to a subject, encompassing a human (see for example, paragraphs 0012, 0033, and 0111 at pages 4, 12, 33, and 103).
Genentech does not clearly state what version, enantiomer, or mix thereof of NAT is used (D, L, or DL (as a racemic mixture)).
However, Yu et al teach that N-acetyl-DL-tryptophan is a known stabilizer (see for example the abstract).
Genentech does not explicitly point to the use of 10mM L-Met. However, Genentech does teach formulations using 5mM L-Met and formulations using 20mM L-Met, as discussed and cited above, thus suggesting to the artisan predictable success with use of L-Met in said formulation at any concentration within the range of 5-20mM.
Alavattam et al teach formulations comprising a protein in combination with a compound that prevents oxidation of the protein, said formulation comprising L-Met at varying concentrations of 10mM-100mM L-Met, pointing out that L-Met at concentrations of 10, 25, 50, and 100mM all reduced oxidation of the protein (such as an antibody) (see for example, paragraphs 0265-0267 at page 25 and the abstract).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches said formulations are helpful for stabilizing a protein such as an antibody. Where Genentech does not explicitly specify the enantiomer type/mix of NAT used, it would have been obvious to try each of the 3, finite options (D, L, and DL), where the artisan would have been particularly led to try N-acetyl-DL-tryptophan (DL-NAT) in light of the teachings of Yu et al that the DL racemic mixture is a known stabilizer. Where Genentech makes obvious the use of 5-20mM L-Met, the artisan would have been particularly led to try a concentration of 10mM in light of the teachings of Alavattam et al, teaching the successful use of 10, 25, 50, and 100mM L-met in formulations for stabilizing protein such as an antibody, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Regarding claim 21, Genentech further teaches that the antibody present in the formulation may be an lgG1, lgG2, lgG3 or lgG4 (see for example, paragraphs 79 and 97 at pages 22-23 and 28-29 and claims 1-15 at pages 125-126).
Regarding claim 22, Genentech teaches that the antibody may be polyclonal, monoclonal, human, chimeric, or humanized (see for example, paragraph 0012 at page 4 and claims 1-15 at pages 125-126).
Regarding claim 25, Genentech teaches formulations comprising NAT and L-Met. Genentech teaches test results demonstrating that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress, where oxidation of the W52 residue was reduced in samples containing NAT relative to the amount of W52 oxidation observed in samples lacking NAT (0 mM NAT added with no mention of adding L-Met, such that the test was presumed to use formulations lacking L-Met) (see for example, paragraph 0293, Figure 1, and Tables 2-3 at pages 107-108 and 1/23). Where the test formulation comprising NAT is shown to protect the W52 residue from oxidation, the artisan would have expected a formulation comprising NAT and L-Met to predictably protect the W52 residue from oxidation.
Regarding claim 26, Genentech, Yu et al, and Alavattam et al teach the formulation of claim 25. Genentech further teaches that the oxidation of the W52 residue is reduced by 43% in a formulation of 0.1mM NAT (see for example, paragraph 0293 and Table 3 at pages 107-108).
Regarding claim 27, Genentech teaches that in some embodiments, the protein (e.g., the antibody) concentration in the formulation is about 1 mg/mL to about 250 mg/mL (see for example, paragraph 0108, page 32).
Regarding claim 28, Genentech teaches that in some embodiments, the formulation has a pH of about 4.5 to about 7.0 (see for example, paragraphs 0024 and 0110 at pages 6 and 33).
Regarding claims 29 and 30, Genentech teaches that in some embodiments, the liquid formulation further comprises one or more excipients selected from the group consisting of a stabilizer, a buffer, a surfactant, and a tonicity agent (see for example, paragraphs 0011, 0014, 0024, 0028-0029, 0033, 0069, and 0210 at pages 4, 5, 6, 8-9, 12, 19, and 65).
Regarding claim 32, Genentech teaches that the liquid formulation can be administered intravenously or subcutaneously [to a mammal in need, preferably a human] (see for example, paragraphs 0217 and 0255 at pages 67-68 and 94).
Claim(s) 12 is/are rejected under 35 U.S.C. 103 as being obvious over Genentech in view of Yu et al and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of University of Arizona ((The Biology Project: Antibody structure (2000); obtained from: https://biology.arizona.edu/immunology/tutorials/antibody/structure.html?ref=1b3p6k) and Sela-Culang et al (Front Immunol. 2013 Oct 8;4:302. doi: 10.3389/fimmu.2013.00302).
Regarding claim 12, Genentech teaches that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress (see for example, paragraph 0293 and Tables 2-3 at pages 107-108).
Genentech does not teach that the W52 residue is in the variable region and does not explicitly teach that variable region tryptophan residues are protected from oxidation.
However, University of Arizona teaches that residue 52 is in the variable region (see for example, the figures titled ‘Heavy-chain V region’ and “Light-chain V region’). This is further supported by Sela-Culang et al which teaches that kabat, chothia, and IMGT tend to have very similar identification of the variable region and CDRs (see for example, figure 3). Therefore, the artisan would have expected residue 52 to be in the variable region, such that in teaching that NAT protects residue W52 from oxidation, the artisan would have understood Genentech to teach that NAT protects one or more tryptophan residues in the variable region from oxidation.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Genentech, Yu et al, Alavattam et al, University of Arizona, and Sela-Culang et al. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches that this formulation reduced oxidation of the W52 residue which is desirable because such oxidation can lead to a loss of function of the antibody and/or impact the formulation safety and efficacy (see for example, paragraph 0003 at page 1 bridging page 2). The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Claim 20 is rejected under 35 U.S.C. 103 as being obvious over Genentech, Yu et al, and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of Stracke et al (MAbs. 2014;6(5):1229-42. doi: 10.4161/mabs.29601; IDS dated 05/19/2021).
Regarding claim 20, Genentech in view of Yu et al and Alavattam et al teaches the formulation of instant claim 1.
Genentech, while teaching that L-Met reduces oxidation of methionine residues (see for example, paragraph 0004 at page 2), does not specifically discuss prevention/reduction of oxidation of the M252 residue.
However, Stracke et al teach that oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels (see abstract at page 1229 and page 1230). Stracke et al further teach that the oxidation reaction was quenched by addition of l-methionine (see the Results and Conclusion sections at pages 1231-1239).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches said formulations are helpful for stabilizing a protein such as an antibody. Where Genentech does not explicitly specify the enantiomer type/mix of NAT used, it would have been obvious to try each of the 3, finite options (D, L, and DL), where the artisan would have been particularly led to try N-acetyl-DL-tryptophan (DL-NAT) in light of the teachings of Yu et al that the DL racemic mixture is a known stabilizer, which specifically guides the artisan to the DL racemic mixture. Where Genentech makes obvious the use of 5-20mM L-Met, the artisan would have been particularly led to try a concentration of 10mM in light of the teachings of Alavattam et al, teaching the successful use of 10, 25, 50, and 100mM L-met in formulations for stabilizing a protein such as an antibody, as discussed above. Moreover, the formulation resulting from the combined references would be expected to perform the same functions/achieve the same results as the claimed formulation because function inherently flows from structure, such that if the formulation resulting from the combined references were argued to fail to function as claimed, the instant claims would likely to fail to meet the requirements of 25 USC §112(a). Because the structure/composition of the prior art formulation makes obvious the instantly claimed formation, and because function necessarily flows from structure such that the properties of the composition are inseparable from the product, the prior art formulation would have been and is presumed to perform the same function/achieve the same results as the instantly claimed formulation. Further, where Genentech teaches that L-methionine reduces oxidation of methionine residues in the formulation and where Stracke et al further teach that L-methionine reduces oxidation of the M252 residue which improves aspects of the formulation, as enumerated above, one of ordinary skill in the art would have expected the addition of L-methionine as taught in Genentech to function to reduce oxidation of the M252 residue and would have been motivated to reduce oxidation of that residue by addition of L-methionine in order to prevent reduced affinity to FcRn and faster plasma clearance related to M252 oxidation. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Claim(s) 19 is/are rejected under 35 U.S.C. 103 as being obvious over Genentech in view of Yu et al and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of Bertolotti-Ciarlet et al (Mol Immunol. 2009 May;46(8-9):1878-82. doi: 10.1016/j.molimm.2009.02.002).
Regarding claim 19, Genentech teaches that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress (see for example, paragraph 0293 and Tables 2-3 at pages 107-108). Stracke et al teach that the M252 residue, in the Fc region, is protected by addition of L-met (which quenches oxidation; see for example, the Results and Conclusion sections at pages 1231-1239).
Genentech does not teach that the W52 residue is in the variable region and does not explicitly teach that variable region tryptophan residues are protected from oxidation.
However, Bertolotti-Ciarlet et al teach that the Fc region is made up of domains of the constant region and further teaches that the Fc region, specifically the CH2 portion, has two conserved methionine residues, one of which is the M252 residue (see for example, page 1878).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Genentech, Yu et al, Alavattam et al, Stracke et al, and Bertolotti-Ciarlet et al. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches a formulation comprising a protein (which can be an antibody), NAT, and L-Met for reducing oxidation, where Stracke et al teach that L-met reduces oxidation of the M252 residue located in the Fc region, which Bertolotti-Ciarlet et al teach is in the constant region. Where the L-Met in the formulation of Genentech as modified by Alavattam et al is present in the recited concentration and is used for the same purpose (stabilization and reduction of oxidation), the artisan would have had a reasonable expectation that methionine residues in the constant region (such as the recited M252 residue) would have been protected from oxidation (as supported by Stracke et al in view of Bertolotti-Ciarlet et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Double Patenting
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.
Claims 1, 21-22, 25-30, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-38, 40-41, 78-79, 93, and 96 of copending application No. 18/300,169 [US-20230406930-A1] (reference A) in view of ‘Genentech’ (WO 2017/117304 A1; IDS dated 05/19/2021) in view of Alavattam et al (US 2014/0314778 A1; IDS dated 05/19/2021).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 1, reference A teaches by claiming a liquid pharmaceutical composition, formulated for intravenous administration, comprising a bispecific antibody (which may be an IgG such as an IgG1 that is monoclonal, human, humanized, or chimeric, present at about 10mg/ml or less), a surfactant, methionine, and a carrier, wherein the pharmaceutical composition has a pH of about 5.5 or 5.8, and wherein the bispecific antibody is at a concentration of about 10 mg/ml or less, (ii) the surfactant is at a concentration from about 0.05% to about 0.12% w/v, and (iii) the methionine is at a concentration of about 10 mM, wherein the pharmaceutical composition further comprises an antioxidant, which may be N-acetyl-DL-tryptophan at a concentration between 0.1 and 0.5 mM (see reference A’s claims 37-38, 40-41, 78-79, 93, and 96; note that the surfactant would read upon the instantly claimed excipient (which may be a surfactant) of instant claims 29-30).
Reference A does not claim certain limitations, such as that the methionine is L-Methionine.
However, Genentech teaches that L-Met may be used with NAT in formulations to reduce protein (antibody) oxidation, as discussed in the rejections under 35 USC §103, above (see for example, paragraphs 0107, 0326 and 0328-0329 at pages 32, 115-116 of Genentech).
While Genentech discloses a range of L-Met concentrations including 10mM, Alavattam et al specifically guide the artisan to a using 10mM L-Met to reduce oxidation (see for example, paragraphs 0265-0267 at page 25 and the abstract; as discussed in the rejections under 35 USC §103 above).
Regarding claim 21, reference A claims that the antibody in the formulation may be an IgG1 (see for example, claims 37 and 78-79 of reference A).
Regarding claim 22, reference A claims that the antibody may monoclonal, human, humanized, or chimeric (see for example, claims 37 and 92 of reference A).
Regarding claim 25, Genentech teaches that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress, where oxidation of the W52 residue was reduced in samples containing NAT relative to the amount of W52 oxidation observed in samples lacking NAT (0 mM NAT added with no mention of adding L-Met, such that the test was presumed to use formulations lacking L-Met (see for example, paragraph 0293, Figure 1, and Tables 2-3 at pages 107-108 and 1/23). Where the test formulation comprising NAT is shown to protect the W52 residue from oxidation, the artisan would have expected a formulation comprising NAT and L-Met to predictably protect the W52 residue from oxidation.
Regarding claim 26, reference A, Genentech, and Alavattam et al teach the formulation of claim 25. Genentech further teaches that the oxidation of the W52 residue is reduced by 43% in a formulation of 0.1mM NAT (see for example, paragraph 0293 and Table 3 at pages 107-108).
Regarding claim 27, Genentech teaches that in some embodiments, the protein (e.g., the antibody) concentration in the formulation is about 1 mg/mL to about 250 mg/mL (see for example, paragraph 0108, page 32).
Regarding claim 28, Genentech teaches that in some embodiments, the formulation has a pH of about 4.5 to about 7.0 (see for example, paragraphs 0024 and 0110 at pages 6 and 33).
Regarding claim 29 and 30, Genentech teaches that in some embodiments, the liquid formulation further comprises one or more excipients selected from the group consisting of a stabilizer, a buffer, a surfactant, and a tonicity agent (see for example, paragraphs 0011, 0014, 0024, 0028-0029, 0033, 0069, and 0210 at pages 4, 5, 6, 8-9, 12, 19, and 65).
Regarding claim 32, Genentech teaches that the liquid formulation can be administered intravenously or subcutaneously [to a mammal in need, preferably a human] (see for example, paragraphs 0217 and 0255 at pages 67-68 and 94). Reference A claims that the formulation may be suitable for intravenous administration (see for example, claims 37-38 of reference A).
Regarding claim 34, Genentech teaches a method of reducing oxidation of a polypeptide in an aqueous formulation (and a kit comprising the liquid formulation, see for example, paragraphs 0019 and 0029 at pages 6 and 8 bridging 9) comprising adding an amount of N-acetyltryptophan (NAT) to the formulation (see for example, page 4 at paragraph 8), at a concentration of 0.1-5 mM (see for example, page 4 at paragraph 9), wherein the oxidation of the polypeptide is reduced by 50-99% (see for example, page 4 at paragraph 10). The formulation comprises protein (which may be an antibody (see for example, page 2 at paragraph 0003 and claim 14 at page 126)) wherein addition of NAT to formulations has resulted in reduction of methionine residue oxidation in proteins and peptides (see for example claim 1 and paragraphs 0003-0004 and 0008 at pages 1-2, 4, 125); further note that formulations comprising 0.3 mM NAT and 5mM L-Met or 1.0 mM NAT and 5 mM L-Met have been taught and suggested as formulations to test and to use to reduce oxidation/oxidative stress (see for example, paragraphs 0107, 0326 and 0328-0329 at pages 32, 115-116). In some embodiments, the formulation is a pharmaceutical formulation suitable for administration to a subject (see for example, paragraphs 0012 and 0033 at pages 4, 12, and 103).
Genentech does not explicitly point to the use of 10mM L-Met. However, Genentech does teach formulations using 5mM L-Met and formulations using 20mM L-Met, as discussed and cited above, thus suggesting to the artisan predictable success with use of L-Met in said formulation at any concentration within the range of 5-20mM.
Alavattam et al teach formulations comprising a protein in combination with a compound that prevents oxidation of the protein, said formulation comprising L-Met at varying concentrations of 10mM-100mM L-Met, pointing out that L-Met at concentrations of 10, 25, 50, and 100mM all reduced oxidation of the protein (such as an antibody) (see for example, paragraphs 0265-0267 at page 25 and the abstract).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches said formulations are helpful for stabilizing a protein such as an antibody. Where Genentech does not explicitly specify the enantiomer type/mix of NAT used, it would have been obvious to try each of the 3, finite options (D, L, and DL), where the artisan would have been particularly led to try N-acetyl-DL-tryptophan (DL-NAT) in light of the claims of reference A. Where Genentech makes obvious the use of 5-20mM L-Met, the artisan would have been particularly led to try a concentration of 10mM in light of the teachings of Alavattam et al, teaching the successful use of 10, 25, 50, and 100mM L-met in formulations for stabilizing protein such as an antibody, as discussed above. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Claim 12 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-38, 40-41, 78-79, 93, and 96 of copending application No. 18/300,169 [US-20230406930-A1] (reference A) in view of Genentech and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of University of Arizona ((The Biology Project: Antibody structure (2000); obtained from: https://biology.arizona.edu/immunology/tutorials/antibody/structure.html?ref=1b3p6k) and Sela-Culang et al (Front Immunol. 2013 Oct 8;4:302. doi: 10.3389/fimmu.2013.00302).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 12, Reference A, Genentech, and Alavattam et al teach the formulation of instant claim 1. Genentech further teaches that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress (see for example, paragraph 0293 and Tables 2-3 at pages 107-108).
Genentech does not teach that the W52 residue is in the variable region and does not explicitly teach that variable region tryptophan residues are protected from oxidation.
However, University of Arizona teaches that residue 52 is in the variable region (see for example, the figures titled ‘Heavy-chain V region’ and “Light-chain V region’). This is further supported by Sela-Culang et al which teaches that kabat, chothia, and IMGT tend to have very similar identification of the variable region and CDRs (see for example, figure 3). Therefore, the artisan would have expected residue 52 to be in the variable region, such that in teaching that NAT protects residue W52 from oxidation, the artisan would have understood Genentech to teach that NAT protects one or more tryptophan residues in the variable region from oxidation.
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of Genentech, Yu et al, Alavattam et al, University of Arizona, and Sela-Culang et al. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches that this formulation reduced oxidation of the W52 residue which is desirable because such oxidation can lead to a loss of function of the antibody and/or impact the formulation safety and efficacy (see for example, paragraph 0003 at page 1 bridging page 2). The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Claim 20 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-38, 40-41, 78-79, 93, and 96 of copending application No. 18/300,169 [US-20230406930-A1] (reference A) in view of Genentech and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of University of Arizona ((The Biology Project: Antibody structure (2000); obtained from: https://biology.arizona.edu/immunology/tutorials/antibody/structure.html?ref=1b3p6k) and Sela-Culang et al (Front Immunol. 2013 Oct 8;4:302. doi: 10.3389/fimmu.2013.00302).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 20, reference A, Genentech, and Alavattam et al teach the formulation of instant claim 1.
Genentech, while teaching that L-Met reduces oxidation of methionine residues (see for example, paragraph 0004 at page 2), does not specifically discuss prevention/reduction of oxidation of the M252 residue.
However, Stracke et al teach that oxidation of Fc methionines Met252 and Met428 is frequently observed, which leads to reduced affinity to FcRn and faster plasma clearance if present at high levels (see abstract at page 1229 and page 1230). Stracke et al further teach that the oxidation reaction was quenched by addition of l-methionine (see the Results and Conclusion sections at pages 1231-1239).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of the combined references. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches said formulations are helpful for stabilizing a protein such as an antibody. Where Genentech does not explicitly specify the enantiomer type/mix of NAT used, it would have been obvious to try each of the 3, finite options (D, L, and DL), where the artisan would have been particularly led to try N-acetyl-DL-tryptophan (DL-NAT) in light of the claims of reference A which specifically guide the artisan to the DL racemic mixture. Where Genentech makes obvious the use of 5-20mM L-Met, the artisan would have been particularly led to try a concentration of 10mM in light of the teachings of Alavattam et al, teaching the successful use of 10, 25, 50, and 100mM L-met in formulations for stabilizing a protein such as an antibody, as discussed above. Moreover, the formulation resulting from the combined references would be expected to perform the same functions/achieve the same results as the claimed formulation because function inherently flows from structure, such that if the formulation resulting from the combined references were argued to fail to function as claimed, the instant claims would likely to fail to meet the requirements of 25 USC §112(a). Because the structure/composition of the prior art formulation makes obvious the instantly claimed formation, and because function necessarily flows from structure such that the properties of the composition are inseparable from the product, the prior art formulation would have been and is presumed to perform the same function/achieve the same results as the instantly claimed formulation. Further, where Genentech teaches that L-methionine reduces oxidation of methionine residues in the formulation and where Stracke et al further teach that L-methionine reduces oxidation of the M252 residue which improves aspects of the formulation, as enumerated above, one of ordinary skill in the art would have expected the addition of L-methionine as taught in Genentech to function to reduce oxidation of the M252 residue and would have been motivated to reduce oxidation of that residue by addition of L-methionine in order to prevent reduced affinity to FcRn and faster plasma clearance related to M252 oxidation. The artisan would have had a reasonable expectation of success based on the cumulative disclosure of these prior art references.
Claim 19 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-38, 40-41, 78-79, 93, and 96 of copending application No. 18/300,169 [US-20230406930-A1] (reference A) in view of Genentech and Alavattam et al, as applied to claims 1, 21-22, 25-30, 32, and 34 above, in further view of Bertolotti-Ciarlet et al (Mol Immunol. 2009 May;46(8-9):1878-82. doi: 10.1016/j.molimm.2009.02.002).
This is a provisional nonstatutory double patenting rejection.
Regarding claim 19, Reference A, Genentech, and Alavattam et al teach the formulation of claim 1. Genentech further teaches that NAT was able to protect the W52 residue from oxidation resulting from AAPH stress (see for example, paragraph 0293 and Tables 2-3 at pages 107-108). Stracke et al teach that the M252 residue, in the Fc region, is protected by addition of L-met (which quenches oxidation; see for example, the Results and Conclusion sections at pages 1231-1239).
Genentech does not teach that the W52 residue is in the variable region and does not explicitly teach that variable region tryptophan residues are protected from oxidation.
However, Bertolotti-Ciarlet et al teach that the Fc region is made up of domains of the constant region and further teaches that the Fc region, the CH2 portion, has 2 conserved methionine residues, one of which is the M252 residue (see for example, page 1878).
It would have been prima facie obvious to the person of ordinary skill in the art to arrive at the claimed invention from the disclosures of reference A, Genentech, Alavattam et al, Stracke et al, and Bertolotti-Ciarlet et al. The artisan would have been motivated to make and use the invention as claimed because Genentech teaches a formulation comprising a protein (which can be an antibody), NAT, and L-Met for reducing oxidation, where Stracke et al teach that L-met reduces oxidation of the M252 residue located in the Fc region, which Bertolotti-Ciarlet et al teach is in the constant region. Where the L-Met in the formulation of Genentech as modified by Alavattam et al is present in the recited concentration and is used for the same purpose (stabilization and reduction of oxidation), the artisan would have had a reasonable expectation that methionine residues in the constant region (such as the recited M252 residue) would have been protected from oxidation (as supported by Stracke et al in view of Bertolotti-Ciarlet et al). The artisan would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
Applicants Arguments and Responses:
A. Applicant argues for withdrawal of the rejections over Genentech, Yu, and Alavattam (see pages 7-10 of the 02/27/2026 remarks). Applicant alleges surprising results (citing tables 3 and 6), arguing L-Met and NAT result in a significantly larger decrease in oxidation of protein (antibody), where said results are argued to overcome the rejections under 35 USC §103 and alleges the prior art references do not teach and make obvious a formulation with the claimed concentration of NAT and L-Met, further alleging no reason to combine Genentech (understood to be what Applicant refers to as Sharma in the remarks) and Alavattam.
Response: Genentech teaches the desirability of a formulation comprising NAT at the claimed concentration with L-Met to reduce oxidation of protein/antibody, where the artisan, seeing that Genentech teaches a range of L-Met from 5mM to an upper final concentration of 20mM, would have looked to the art for appropriate concentrations to use in the formulation of Genentech and would have found that Alavattam guides to 10mM L-Met as being effective at reducing oxidation of antibody/protein. Thus, the resulting formulation appears to be chemically/structurally identical to the instantly claimed formula. The MPEP provides that, “[p]roducts of identical chemical composition can not have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id,” (see MPEP section 2112.01 (II)). The MPEP further provides that:
"[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). In In re Crish, 393 F.3d 1253, 1258, 73 USPQ2d 1364, 1368 (Fed. Cir. 2004), the court held that the claimed promoter sequence obtained by sequencing a prior art plasmid that was not previously sequenced was anticipated by the prior art plasmid which necessarily possessed the same DNA sequence as the claimed oligonucleotides. The court stated that "just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel." Id. See also MPEP 2112(I) with regard to inherency and product-by-process claims and MPEP § 2141.02 with regard to inherency and rejections under 35 U.S.C. 103,”
(see MPEP 2112(I)).
This is further not found persuasive because applicant’s allegedly unexpected results are not actually unexpected. Recall that Genentech teaches formulations comprising NAT and L-Met to reduce protein (antibody) oxidation (see the rejections under 35 USC §103 above for further detail; see further the refences cited in the conclusion section of this Office Action as relevant, but not relied upon for evidence that this interaction/combination was known in the art). Thus, applicant’s allegedly unexpected results are expected from the prior art. They represent a standard result that the artisan would routinely arrive at, given that it has been a standard formulation since at least 2017 (the time of publication of Genentech and the relevant, but not relied upon references).
MPEP 716.02 (b) teaches that the burden is on applicant to establish their results are unexpected and significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."). Applicant is merely concluding that their results are superior without showing statistical and practical significance. See MPEP 716.02 for direction on how to properly establish unexpected results for the claimed invention. To be of probative value, objective evidence of unexpected results must be factually supported by actual proof. See MPEP 716.01(c). Further note that the results pointed to do not clearly demonstrate the individual effects of the addition of L-Met and the individual effects of added NAT with respect to oxidation. Thus it is not possible to determine the presence or absence of synergy. The results of the formulation having 0.3mM NAT and 10 mM L-Met are not clearly statistically significant over the formulation having 0.3mM NAT and 5 mM L-Met. The results of table 6 do not contain a formulation commensurate in scope with what is claimed (the only concentration of L-Met is 5mM). Note also that arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965).
Genentech does teach that the formulation is stable, with respect to oxidation, with a total concentration of 20 mM L-Met and teaches that the goal of the formulation is to reduce oxidation of antibody residues while being suitable for administration to a subject (see for example, paragraph 0012) where the subject is defined to include a human (see for example, paragraph 0111). Applicant alleges that this teaching can only apply to an in vitro test. Even if that is true (which is not conceded), it motivates the artisan to look to the art for intermediate L-Met concentrations which could be used in the formulation of Genentech for better protection against oxidation while remaining suitable for administration to a human subject.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the artisan would have found it obvious to look to the prior art to determined known concentrations of L-Met for reducing oxidation of residues in an antibody/protein because Genentech teaches a formula that reduces oxidation residues in an antibody/protein by including NAT and L-Met and would have found it obvious to modify the formula of Genentech according to Alavattam because Alavattam teaches 10 mM L-Met successfully reduces oxidation of residues in an antibody/protein.
Therefore, this is not deemed to be sufficient to overcome the rejections of record, which are presently maintained.
B. Applicant reiterates the arguments and allegations addressed in point A above as a basis for requesting withdrawal of the rejections over: 1. Genentech, Yu, Alavattam, and University of Arizona (understood to be what Applicant refers to as the Biology Project) and Sela-Culang (see for example, page 11 of the 02/27/2026 remarks); 2. Genentech, Yu, Alavattam, Stracke (see for example, pages 11-12 of the 02/27/2026 remarks); and 3. Genentech, Yu, Alavattam, and Bertolotti-Ciarlet (see for example, page 13 of the 02/27/2026 remarks) .
Response: For the reasons iterated in the response to point A above, these arguments/allegations are believed to be rebutted and the arguments/allegations, while having been fully considered, are deemed unpersuasive. Therefore, the rejections of record are maintained.
C. Applicant requests rejections for double patenting be held in abeyance (pages 13-14 of the 02/27/2026 remarks).
Response: This has been fully considered but is not found to be persuasive. Applicant’s attention is respectfully directed to M.P.E.P. § 804(I)(B)(1), which states: “A complete response to a nonstatutory double patenting (NSDP) rejection is either a reply by applicant showing that the claims subject to the rejection are patentably distinct from the reference claims or the filing of a terminal disclaimer in accordance with 37 CFR 1.321 in the pending application(s) with a reply to the Office action (see MPEP § 1490 for a discussion of terminal disclaimers). Such a response is required even when the nonstatutory double patenting rejection is provisional.” “As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application’s claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held in abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated. Replies with an omission should be treated as provided in MPEP § 714.03.Therefore, an application must not be allowed unless the required compliant terminal disclaimer(s) is/are filed and/or the withdrawal of the nonstatutory double patenting rejection(s) is made of record by the examiner.” See MPEP § 804.02, subsection VI, for filing terminal disclaimers required to overcome nonstatutory double patenting rejections in applications filed on or after June 8, 1995. (emphasis added). Accordingly, the rejection is maintained and is expressly not held in abeyance.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Please note that the art cited on the 05/19/2021 IDS, including that cited in the Written Opinion of the International Search Authority for PCT/US2019/045420, is held to be pertinent to the claims as presently drafted.
Hagerman et al (as cited in the 09/11/2024 office action) teaches that Tryptophan’s (Trp) unique hydrophobic and structural properties make it an important antigen binding motif when positioned in complementarity-determining regions (CDRs) of monoclonal antibodies (mAbs). Oxidation of Trp residues within the CDR can deleteriously impact antigen binding, particularly if the CDR conformation is altered. Hagerman et al evaluated the conformational and functional impact of Trp oxidation for two mAb subtypes, which is essential in determining the structure-function relationship and establishing appropriate analytical control strategies during protein therapeutics development.
US 20170239355 A1 (as cited on the 05/19/2021 IDS) teaches methods and formulations comprising a protein comprising solvent accessible amino acid residues susceptible to oxidation wherein N-acetyl tryptophan (NAT) is used to prevent oxidation of the protein. The invention also provides methods for making such formulations and methods of using such formulations. Methods to measure degradation of NAT in protein formulations are also provided.
Lobner et al teach that the Fc region comprises only constant region residues and further suggests that residue M252 would be expected to be in the Fc, constant CH2 region(see for example, pages 114-115).
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/Ashley Gao/
Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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