DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 8/10/2026 to claims 1, 18, 23, 58, and 65 have been entered. Claims 2, 6-10, 12, 13, 15, 16, 21, 24-50, 53-57, 59, 60, 62-64, and 66-68 are canceled. Claims 1-5, 11, 14, 17-20, 22, 23, 51, 52, 58, 61, and 65 remain pending, and are subject to the election requirement dated 6/10/2026.
Election/Restrictions
Applicant’s election without traverse of Group I, presently claims 1-5, 11, 14, 17-20, 22, 23, 51, and 52, in the reply filed on 8/10/2026 is acknowledged.
Claims 58, 61, and 65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/10/2026.
Claims 1-5, 11, 14, 17-20, 22, 23, 51, and 52 are under consideration on the merits.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites “belatacep”, which in this context is likely a typo for “belatacept”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 14 and 17 are 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.
Claim 14 recites the limitation "the third final temperature”, and claim 17 recites the limitation “the second temperature”. Both claims 14 and 17 depend from claim 1, but there is insufficient antecedent basis for these limitations in the claims. Correction is required.
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 4, 11, 18, 19, 22, 23, 51, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Putics et al. (WO 2017/021493; provided in the IDS dated 10/06/2023).
Putics teaches a method of increasing galactosylation (e.g. a type of glycosylation) of a model recombinant protein (i.e. an antibody) made by culturing CHO cells under suitable conditions (e.g. osmolarity < 400 mOsm/kg), at a pH range of 7.05-7.15 and at 37°C (Example 1.1 at pages 27-30 and subheading 2.1 at pages 31-34), reading in-part on claims 1, 2, 51, 52. In a separate embodiment, Putics teaches belatacept as an exemplary recombinant fusion protein (page 11, lines 10-20), reading on claim 1. Putics teaches an initial viable cell density (VCD) of 4.0-7.0 x 106 cells/ml (page 35, lines 6-10), reading on claim 4 in light of Applicant’s definition of “about” at [0032] of the specification. Putics teaches maintaining the pH from 7.15-7.25 for a first time period of 60-80 hours (page 18, lines 11-16), reading on claim 11. Putics teaches further adding 0.002-0.1 mM manganese chloride (page 5 ; page 35, lines 1-4), reading on claim 19 and reading in-part on claim 20.
Regarding claim 1, it would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the unspecified recombinant antibody of Putics with the belatacept envisioned by Putics in Putics’s methods. A person of ordinary skill in the art would have had a reasonable expectation of success and would have been motivated to do so because Putics expressly considers the substitution of belatacept as an exemplary species of recombinant antibody, and would predictably yield a method of increasing the galactosylation of belatacept.
Regarding the preamble of claim 1 and dependent claims 18, 22, and 23, claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure. See M.P.E.P. § 2111.02 and 2111.04. In the instant case, independent claim 1 and so dependent claims 18, 22, and 23 recite a manipulatively complete process. Therefore, the preamble of claim 1 and the wherein clauses of claims 18 and 22 do not further manipulatively limit the claimed process as such statements amount to the intended outcome. Alternatively, because Putics teaches every manipulative limitation of claim 1, then Putics is reasonably presumed inherently capable of meeting the preamble of claim 1 and the wherein clauses of claims 18, 22, and 23 all reciting an intended outcome therein absent any showing to the contrary See M.P.E.P. § 2112.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claims 3, 5, 14, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Putics as applied to claim 1 above, and further in view of Thuduppathy et al. (WO 2014/170866A2; Reference N).
The teachings of Putics are relied upon as set forth above. Putics further teaches a cultivation temperature of 37°C. (page 28, lines 13-17), reading in-part on claims 3, 5, 14, and 17. Putics further teaches a second period of time to maintain a second pH for 6-11 days (i.e. 144-264 hours) (page 18, lines 18-30), reading on the second time range of claim 17 and reading in-part on the third time range of claim 14.
Regarding claim 3, Putics does not teach wherein the suitable conditions further
comprise an initial temperature set point between about 35°C and about 37°C, a second temperature set point between about 32°C and about 34°C, and a third temperature set point between about 30°C to about 32°C. Regarding claim 5, Putics does not teach wherein the suitable conditions comprise an initial temperature set point of about 36°C, a second temperature set point of about 33°C, and a third temperature set point of about 31°C. Regarding claim 14, Putics does not teach wherein the third final temperature set point is about 31°C and occurs after about 240 hours.
Regarding claim 17, Putics does not teach wherein the second temperature set point is
about 33°C after about 140 hours.
Thuduppathy teaches methods of culturing cells to produce glycoproteins such as antibodies having increased galactosylation content (Abstract; Example 1). Thuduppathy teaches a first temperature of 35-37°C and a second temperature that is reduced by 2-7°C (claim 4), reading on the first and second temperatures of claims 3, 5, and 17 and reading in-part on the third temperature range of claims 3, 5, and 14. Thuduppathy teaches that a temperature downshift increases the galactosylation of the protein of interest (claim 5 and the Abstract), reading on claims 3, 5, 14, and 17.
Regarding claims 3, 5, and 17, it would have been obvious to a person of ordinary skill in the art before the invention was filed to add the second temperature range of Thuduppathy to the recombinant protein production methods of Putics. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Putics and Thuduppathy are directed towards methods of producing antibodies having increased galactosylation. The skilled artisan would have been motivated to do so because Thuduppathy teaches that a temperature downshift increases the galactosylation of the protein of interest, and so addition would predictably improve upon the galactosylation of the protein(s) of interest in Putics’ methods.
Regarding the third temperature range of claims 3, 5, and 14, repetition of steps previously recited within a claim is on its own not inventive because it merely requires employing the well-known maxim, “If at first you don’t succeed, try, try again.” See Perfect Web Techs., Inc. v. InfoUSA Inc., 92 U.S.P.Q.2d 1849, 1856 (Fed. Cir. 2009). Repeating steps until a desired result is achieved requires only common sense and so is obvious to try and not inventive. Id. at 1854-55 (citing KSR Int’l Co. v. Teleflex Inc., 82 U.S.P.Q.2d 1385 (U.S. 2007)). See M.P.E.P. § 2143(I)(E). In this case, Thuduppathy clearly teaches the known benefits of a temperature downshift to improve galactosylation of recombinantly-produced proteins such as antibodies, and so a third temperature set point as claimed and in the known temperature reduction range of Thuduppathy must be held prima facie obvious absent any showing of nonobviousness to the contrary.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Claim 20 is rejected under 35 U.S.C. 103 as being unpatentable over Putics as applied to claims 1 and 19 above, and further in view of Leiske et al. (US 10,167,492; Reference A).
The teachings of Putics are relied upon as set forth above.
Regarding claim 20, Putics does not teach a manganese concentration range of about 1.6-15 parts-per-billion (ppb).
Leiske teaches methods of modulating the fucosylated glycan profile of recombinantly-expressed proteins such as antibodies (Abstract and claim 23). Leiske teaches that typical therapeutic antibodies have complex glycoforms possessing fucosylated bi-antennary glycans and that afucosylation enhances antibody-dependent cellular cytotoxicity (ADCC) (Col. 1, lines 26-49), reading on claim 20. Leiske teaches that greater concentrations of manganese (as MnCl2) and higher pH positively correlate to higher levels of afucosylation in antibodies produced from CHO cells (Tables 2 and 3, Fig. 6, and Col. 22, lines 22-26); also Col. 20, lines 53-67), reading on claim 20.
1 part-per-billion (ppb) is approximated as 1 μg/L, in so much that the density of water is about 1 g/cm3 (i.e. 1 g/ml or 1 mg/μl), so: 1 mg/μl * (1000 μg/mg) * (106 μl/L) * (1/109) = 1 μg/L. Therefore, the 50 nM concentration of manganese chloride of Leiske equates to: (50 nM * 125.84 g/mol for anhydrous MgCl2 (CAS Registry number 773-01-5) * (1 mol ÷ 109 nanomole) = 6.29 x 10-6 g/L = 6.29 μg/L, and so Leiske reads on the manganese concentration range of claim 20. Noting that Leiske does not teach a particular MnCl2, in addition to anhydrous MnCl2 both the dihydrate form (CAS Registry number 20603-88-7, 161.87 g/mol) and the tetrahydrate form (CAS Registry number 13446-34-9, 197.91 g/mol) of MnCl2 read on the manganese concentration range of claim 20 at 8.09 μg/L and 9.90 μg/L respectively.
Regarding claim 20, It would have been obvious to a person of ordinary skill in the art before the invention was filed to substitute the higher manganese concentrations of Putics for the lower manganese concentrations of about 6-10 μg/L (i.e. ppb) of Leiske in Putics’ methods. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both Putics and Leiske are directed towards methods of producing antibodies and modulating the glycosylation of said antibodies. The skilled artisan would have been motivated to do so because . Leiske teaches that greater concentrations of manganese (as MnCl2) and higher pH positively correlate to higher levels of afucosylation in antibodies produced from CHO cells and that afucosylation enhances antibody-dependent cellular cytotoxicity (ADCC), and so the reduction of the manganese concentration of Putics would predictably improve upon the afucosylation of the antibodies produced in the method of Putics.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
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 1-5, 11, 14, 17, 18, 22, and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 10, 16, and 17 of copending Application No. 18/041,669 (reference application) as evidenced by Larsen et al. (American Journal of Transplantation (2005); 5: 443–453; Reference U).
Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of the ‘669 Application is in-part the narrower embodiment of the “suitable conditions” of instant claim 1 and 2, and the second and third temperature range and culture times of claims 3, 11, 14, and 17. While claim 1 of the ‘669 Application recites abatacept and not belatacept as set forth in instant claim 1, as evidenced by Larsen, belatacept is structurally identical to abatacept as both are Ig-CTLA4 fusion proteins, except that belatacept possesses L104E and A29Y mutations that increase the binding affinity of belatacept (see Abstract and page 444, the first full paragraph in the left column of Larsen). Therefore, these fusion protein antibodies are so structurally similar and have very close utilities that the ‘699 Application renders instant claims 1 and 2 prima facie obvious; see M.P.E.P. § 2144.09.
Claim 1 of the ‘669 Application reads in-part on the pH range of claims 1 and 2, the viable cell density (VCD) of claims 4 and 5, and the first feed time of claim 11. However, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of Amer. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). In this case, the pH range, VCD, and first feed time of the ‘669 are so close to the ranges of instant claims 1-5 and 11 that that one skilled in the art would have expected them to have the same properties absent any showing to the contrary. M.P.E.P. § 2144.05
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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