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 .
DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/23/2026 has been entered.
Status of the claims
Claims 43-50, 52 and 62-70 are pending and claims 50, 52 and 64-70 are examined on merits in this office action. See the office action of 11/13/2024 for the withdrawal of claims 43-49 and 62-63 as being directed to non-elected invention. Applicants preserve their right to file a divisional on the non-elected subject matter.
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 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 of this title, 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.
Claims 50, 52 and 64-70 are rejected under 35 U.S.C. 103 as obvious over Leister et al (US 2009/0252749) in view of Ichihara et al (MABS 2018).
In regards to claims 50-52 and 64-70, Leister discloses a fusion protein monomer comprising a CTLA4-Ig fusion protein wherein the Ig is a constant region from human IgG1 (paragraph [0262], [0265], [0266], [0291, [0446]). Leister discloses fusion monomer comprising CTLA4 and Fc domain of human immunoglobulin of IgG1 (paragraphs [0503] and [1214]). Leister disclosed pharmaceutical composition of CTLA4-Ig (para [00181], [0197] and [0208] and [0311]). Leister teaches population of CTLA4-Ig monomer wherein the composition is substantially free of CTLA4-Ig dimer and tetramer (Example 4; paragraphs [0013], [0152] and [0635]). Leister teaches that the invention provides for a composition consisting essentially of CTLA4-Ig monomers substantially free of CTLA4-Ig dimers and high molecular weight species (paragraph [0221]). Leister, as described above teaches CTLA4-Ig monomers and pharmaceutical composition with the monomers and also teaches CTLA4-Ig monomer wherein the composition is substantially free of CTLA4-Ig dimer and tetramer. In the reference of Leister, the term substantially free of CTLA4-Ig dimer and tetramer is referred for a population wherein less than 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of CTLA4-Ig dimer and tetramer (i.e. HMW impurities) are present in the population, which encompasses the recitation of purity of “at least 90%” or “more than 90%” or a purity of “more than about 99%” as claimed. It is noted that the recitation “as measured by SE-HPLC” is a product identified by a process limitation, but it is the “product” which is considered for patentability, not the process by which the purity is measured. Regarding the product, Leister discloses the same product (i.e. fusion protein monomer CTLA4-IgG1) and teaches the product having less than 0.1% HMW, which reads on the claimed impurities of HMW. Regarding LMW impurities Leister teaches that in all cases, the LMW impurities are below the detection limit (paragraph [0979]). Moreover, Leister taches Protein A chromatograph for CTLA4-Ig purification (para [1023]) followed by downstream chromatography polishing steps.
Leister does not recite fusion protein having purity of at least 90% or more than 90%, HMWs impurities of less than 0.2% and LMW impurities of less than 0.5%, as measured by SE-HPLC, and as claimed in claims 50, 52 and 64-70.
Ichihara teaches integrated flow-through purification for therapeutic monoclonal antibodies. Ichihara teaches protein A chromatography purification followed by anion exchange chromatograph (AEX) and cation exchange chromatography (CEX)in a flow-throw process, which efficiently remove lower molecular weight impurities with minimal impact on mAb yield (page 326 and Fig.1). Ichihara teaches that adjustment of pH and employing initial pA chromatography followed by AEX and CEX effectively remove HMW and LMW impurities (page 326, Fig 2). Ichihara discloses low molecular weight impurities of less than 0.5% (Table 1) using the process.
Therefore, given the fact purification of recombinant antibody utilizing pA chromatography followed by downstream polishing step for removing HMW and LMW proteins are disclosed by Leister and Ichihara, it would be obvious to one of ordinary skilled in the art to optimize purification steps implementing all known and disclosed purification processes for removing maximum impurities depending on needs with a reasonable expectation of success. Since Leister teaches purification of CTLA4-Ig monomers having less than 0.1% HMW impurities and teaches LMW impurities are below the detection limit, it would be obvious to one of ordinary skilled in the art to easily envisage utilizing pA purified antibody with various downstream polishing steps including AEX and CEX as taught by Ichihara with various optimization to maximize impurity removal with a reasonable expectation of success. One of ordinary skilled in the art would expect the final product would have highly pure CTLA4-Ig monomer with less than 0.2% HMW and less than 0.5% LMW impurities absent showing the the process would not produce such purity.
Moreover, mere purity of a product, by itself, does not render the product unobvious (MPEP 2144.04). Product which differs from prior art only in purity is obvious except when the pure product possesses unexpected properties not possessed by the impure one. Ex parte Gray 10 USPQ 2d 1922, 1925 (BPAI 1989); Ex parte Steelmand 140 USPQ 189; In re King 43 USPQ 400 (CCPA 1939); In re Merz 38 USPQ 143 (CCPA 1938); In re Ridgeway 25 USPQ 202 (CCPA 1935); Ex parte Windhaus 15 USPQ 45 (PO BdPatApp 1931).
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 50, 52 and 64-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10-17 and 18-21 of copending Application No. 18/629,465 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because CTLA4-IgG1 fusion protein having purity over 98% with HMWs of less than 0.1% is obvious form the process claims of copending application ‘465.
Claims 1-7, 10-19 and 21 of copending application disclose separation of CTLA4-IgG1 fusion protein from pre-peak impurity and post-peak impurity by size exclusion high performance liquid chromatography column. Claim 20 of the copending application discloses that the purity of the CTLA4-IgG1 fusion protein with the process is more than 98%, which encompasses the purity of at least 90%, more than 95%, about 97% and more than about 99%. Claims of the copending application disclose separating pre-peak impurity of high molecular weight and/or aggregates and post-peak impurity of low molecular weight and/or fragments (see claim 5), but however, do not mention that the HMWs impurity is less than 0.1% or about 0.09% measured by SE-HPLC. However, since claim 20 of the copending application discloses purity of more than 98%, it is highly expected that the process would provide CTLA4-IgG1 fusion protein having about 99% purity and HMWs of about 0.09% absent showing otherwise by Applicant. The Patent and Trademark Office does not have the facilities and resources to provide the factual evidence needed in order to establish that there is a difference, in the first place, between the purified CTLA4-IgG1 of the copending application and those instantly claimed composition having purified CTLA4-IgG1. The burden is upon applicant to present such factual evidence. See e.g. In re Best (195 USPQ 430 (CCPA 1977)) or Ex parte Phillips (28 USPQ2d 1302 (BPAI 1993)). Further, the product (CTLA4-IgG1 over 90% purity) is disclosed in copending application ‘465 and mere purity of a product, by itself, does not render the product unobvious (MPEP 2144.04). Product which differs from prior art only in purity is obvious except when the pure product possesses unexpected properties not possessed by the impure one. Ex parte Gray 10 USPQ 2d 1922, 1925 (BPAI 1989); Ex parte Steelmand 140 USPQ 189; In re King 43 USPQ 400 (CCPA 1939); In re Merz 38 USPQ 143 (CCPA 1938); In re Ridgeway 25 USPQ 202 (CCPA 1935); Ex parte Windhaus 15 USPQ 45 (PO BdPatApp 1931).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 50, 52 and 64-70 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 8, 12-18, 20, 22-24, 26-27, 29, 31-32, 34 and 36-40 of copending Application No. 18/550,920 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because CTLA4-IgG1 fusion protein having purity over 98% with HMWs of less than 0.1% is obvious form the process claims of copending application ‘465.
Claims 1 of copending application ‘920 disclose a pharmaceutical composition having a pharmacologically active fusion protein. Claim 26 of the copending application ‘920 teaches that the pharmaceutically active fusion protein comprises a receptor selected from CTLA4 fused with constant region of IgG1 (i.e. CTLA4-IgG1 fusion protein). Claim 40 of the copending application teaches the pharmaceutical formulation may comprise momoner having purity of more than 98% as analyzed by SE-HPLC having high molecular weight impurities below 1% as analyzed by SE-HPLC. Therefore, pharmaceutical composition having CTLA4-IgG1 monomer having over 98% purity with impurity of HMWs of less than 1% would be obvious from the claims of copending application ‘920. The claims of copending application does not mention impurity of HMWs of less than 0.1%, but however, claims of the copending application teaches HMWs impurity below 1 and would encompass all impurities lower than 1%. However, mere purity of a product, by itself, does not render the product unobvious (MPEP 2144.04). Product which differs from prior art only in purity is obvious except when the pure product possesses unexpected properties not possessed by the impure one. Ex parte Gray 10 USPQ 2d 1922, 1925 (BPAI 1989); Ex parte Steelmand 140 USPQ 189; In re King 43 USPQ 400 (CCPA 1939); In re Merz 38 USPQ 143 (CCPA 1938); In re Ridgeway 25 USPQ 202 (CCPA 1935); Ex parte Windhaus 15 USPQ 45 (PO BdPatApp 1931).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to argument
Applicant's arguments filed 01/23/2026 have been fully considered and are persuasive to overcome the rejections under 35 USC 112(b) in view of the amendments. However, Applicant’s arguments and amendments are not persuasive to overcome the rejections under 35 USC 103 and the rejection under obviousness non-statutory double patenting rejection.
In regards to double patenting rejection, the rejection is maintained because request to held in abeyance until patentable subject matter has not been identified, is not a substitute of terminal disclaimed. Thus, in the absence of filing a terminal disclaimer, the rejection is maintained.
In regards to 35 USV 103 rejection, Applicant argued that purity thresholds of the presently claimed CTLA4-IgG1 compositions (less than 0.2% of high molecular weight impurities and less than 0.5% low molecular weight impurities) were difficult to achieve. Applicant argued that Leister does not teach or suggest a fusion protein having purity of at least 90% or more than 90% and HMWs less than 0.2% and less that 0.5% of low molecular weight impurities as presently claimed. Applicant argued that Ichihara primarily emphasizes the removal of DNA and HCP, and general aggregate clearance, without teaching the specific HMW/LMW balance achieved by the instant four-column process.
The above arguments have fully been considered but are not found persuasive. As described in the above rejection, Leister disclosed pharmaceutical composition of CTLA4-Ig (para [00181], [0197] and [0208] and [0311]) and discloses composition consisting essentially of CTLA4-Ig monomers substantially free of CTLA4-Ig dimers and high molecular weight species (paragraph [0221]). Leister teaches that the term substantially free of CTLA4-Ig dimer and tetramer is referred for a population wherein less than 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of CTLA4-Ig dimer and tetramer (i.e. HMW impurities) are present in the population, which encompasses the recitation of purity of “at least 90%” or “more than 90%” or a purity of “more than about 99%” as claimed. It is noted that the recitation “as measured by SE-HPLC” is a product identified by a process limitation, but it is the “product” which is considered for patentability. Regarding LMW impurities, Leister teaches that in all cases, the LMW impurities are below the detection limit (paragraph [0979]). Leister taches Protein A chromatograph for CTLA4-Ig purification (para [1023]) followed by downstream chromatography polishing steps. As described above, Ichihara teaches protein A chromatography purification followed by anion exchange chromatograph (AEX) and cation exchange chromatography (CEX)in a flow-throw process, which efficiently remove lower molecular weight impurities with minimal impact on mAb yield (page 326 and Fig.1). Ichihara teaches that adjustment of pH and employing initial pA chromatography followed by AEX and CEX effectively remove HMW and LMW impurities (page 326, Fig 2). Ichihara discloses low molecular weight impurities of less than 0.5% (Table 1) using the process. Therefore, combination of Leister in view of Ichihara as described above, provides utilizing pA purified antibody of Leister with various downstream polishing steps including AEX and CEX as taught by Ichihara with various optimization to maximize impurity removal with a reasonable expectation of success. One of ordinary skilled in the art would expect the final product would have highly pure CTLA4-Ig monomer having similar purity, that is, similar to less than 0.2% HMW and less than 0.5% LMW impurities.
Once a product appearing to be substantially identical is found and a prior art rejection is made, the burden shift to the applicant to show an nonobvious difference (MPEP 2113 II). Moreover, since purified product of CTLA4-Ig having substantially free of HMW molecules has been disclosed by Leister and CTLA4-Ig, substantially free of HMW and LMW are obvious from Leister and Ichihara, the product is obvious in view of the prior art because mere purity of a product, by itself, does not render the product unobvious (MPEP 2144.04). Product which differs from prior art only in purity is obvious except when the pure product possesses unexpected properties not possessed by the impure one. Ex parte Gray 10 USPQ 2d 1922, 1925 (BPAI 1989); Ex parte Steelmand 140 USPQ 189; In re King 43 USPQ 400 (CCPA 1939); In re Merz 38 USPQ 143 (CCPA 1938); In re Ridgeway 25 USPQ 202 (CCPA 1935); Ex parte Windhaus 15 USPQ 45 (PO BdPatApp 1931).
In regards to Applicant’s argument of purity achieved by instant four-column process, it is noted that in the case of product-by-process claims, if a first prior art process is improved to enhance the purity of the product produced by the process, and if the purified product has no structural or functional difference from the products produced by other prior art processes, then the improvement in the first process that improves the purity of the product does not give rise to patentability. See Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). See also MPEP § 2113. See also Ex parte Stern, 13 USPQ2d 1379 (Bd. Pat. App. & Inter. 1987) (Claims to interleukin-2 (a protein with a molecular weight of over 12,000) purified to homogeneity were held unpatentable over references which recognized the desirability of purifying interleukin-2 to homogeneity in a view of a reference which taught a method of purifying proteins having molecular weights in excess of 12,000 to homogeneity wherein the prior art method was similar to the method disclosed by appellant for purifying interleukin-2).
Conclusion
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/SHAFIQUL HAQ/Primary Examiner, Art Unit 1678
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