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
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 01/21/2026 has been entered.
Claim Status
Claim 1 has been amended.
Claims 1-2, 5-6, and 9-20 are under consideration in the instant Office Action..
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 U.S.C. § 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 present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Claims 1-2, 5-6, and 9-20 are rejected under 35 U.S.C. 103 as being unpatentable over Shapiro et al. (US 20180244763 A1, in PTO-892 filed 10/17/2023), in view of Brisbane et al. (US 20100189721 A1, in PTO-892 filed 10/17/2023), Dubey et al. (WO 2020053301 A1, in PTO-892 filed 10/17/2023), and Brovc et al. 2020 (PTO-892 filed on 324/2026).
The instant claims encompass a pharmaceutical composition comprising: an anti-TGF-β antibody, acetate, EDTA, PS80, and sucrose, with a pH of 5.0 ± 0.3 and a method for treating cancer.
Regarding claims 1 and 20, Shapiro teaches an antibody, Ab1, comprised of heavy chains (HCs) with amino acid SEQ ID NO: 1 (Pages 3 and 4) and light chains (LCs) with amino acid SEQ ID NO: 2 (Page 4). Shapiro’s antibody is 100% identical to instant SEQ ID NO: 1 and SEQ ID NO: 2. The two images below are BLAST alignments of amino acid SEQ ID NO: 1 and amino acid SEQ ID NO: 2, each as disclosed in Shapiro et al, and recited in instant claim 1.
The first image below compares the amino acid sequence SEQ ID NO: 1 from Shapiro et al (Query) with amino acid SEQ ID NO: 1 as recited in instant claims 1 (Sbjct). The untitled amino acid sequence between the Query and Sbjct amino acid sequences illustrate identities and differences between Query and Sbjct. Identities mirror the aligned amino acid sequences of Query and Sbjct. Differences are noted as gaps and + symbols. Differences may also be indicated in Query and Sbjct as dash marks. The BLAST amino acid alignment illustrates 100% identity between Query and Sbjct for SEQ ID NO: 1.
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The second image compares the amino acid sequence SEQ ID NO: 2 from Shapiro et al (Query) with amino acid SEQ ID NO: 2 as recited in instant claims 1 and 11 (Sbjct). The untitled amino acid sequence between Query and Sbjct illustrate identities and differences between Query and Sbjct. Identities mirror the aligned amino acid sequences of Query and Sbjct. Differences are noted as gaps and + symbols. Differences may also be indicated in Query and Sbjct as dash marks. The BLAST alignment illustrates 100% identity between Query and Sbjct for SEQ ID NO: 2.
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Regarding claims 1 and 2, Shapiro teaches that amino acid SEQ ID NO: 1 and 2 in antibody aqueous liquid solution compositions are identical to those recited in claim 2.
Regarding claims 1, 9 and 20, Shapiro et al teaches Ab1 aqueous liquid solution compositions from pH 3 to pH 9 ([0102]).
Regarding claims 1 and 13-15, Shapiro teaches a method of treating cancer in a patient in need thereof with a therapeutically effective dose of a single antibody therapeutic or in conjunction with an additional anti-cancer therapeutic ([0191]), at a single dose of 5 mg/kg (Page 15, Table 5) or a combined therapeutic dose at 15 mg/kg (Page 16, Table 6A).
The relevance of Shapiro et al. is set forth above. Shapiro does not teach the specific antibody concentration ranges in mg/ml or for the components comprising acetate, chelating agent, or surfactant. However, that fact does not avoid a finding of prima facie obviousness in light of the overlap of the claimed range. “Selecting a narrow range from within a somewhat broader range disclosed in a prior art reference is no less obvious than identifying a range that simply overlaps a disclosed range.” In re Peterson, 315 F.3d at 1329—30.
Regarding claims 1, 5-6, and 20, Brisbane teaches that antibody aqueous liquid solution compositions comprise surfactant PS80 concentrations from 0.01-0.2% ([0009] and claim 1). Brisbane teaches that antibody aqueous liquid solution compositions comprise antibody concentrations from 20 mg/ml to 300 mg/ml ([0011] and claims 16 and 17). Brisbane teaches that antibody aqueous liquid solution compositions comprise EDTA, a chelating agent, at concentrations of 0.02 mM to 0.200 mM ([0009] and claim 1). Brisbane et al teaches that antibody aqueous liquid solution compositions comprise acetate concentrations from 10-100 mM ([0009] and claim 1, and has a pH range of 5.0 to 7.0, see claim 1. Brisbane also teaches that the stability of antibodies in the recited formulation is “at an optimum in solutions with a pH ranging from 4.5 to 5.5, the SEC-HPLC results and the non-reduced CE-SDS-PAGE results suggest that the optimum stability can be found in the pH range between 5.0 and 6.0”, ([0074]).
The relevance of Shapiro et al. and Brisbane is set forth above. Shapiro and Brisbane do not teach a stabilizing agent, such as sucrose.
Regarding claim 1, Dubey et al teaches that sucrose concentrations in antibody aqueous liquid solution compositions comprise sucrose at concentrations from 5%-15% (Page 2, Line 20 and claim 9).
The components of antibody aqueous liquid solution compositions are as recited above for claims 1-2, 5-6, 9, which read on claims 1, 10-12, 16-19, and 20. Shapiro teaches antibody aqueous liquid solution compositions with an antibody component comprising amino acid SEQ ID NO: 1 and 2 (Pages 3 and 4). Shapiro teaches an article of manufacture or a kit comprising antibody aqueous liquid solution compositions ([0163]).
The relevance of Shapiro, Brisbane, and Dubey is set forth above. However, they do not teach the newly amended claim limitation wherein the concentration of the chelating agent EDTA has been narrowed to 10 µM. Brovc et al. remedies this deficiency.
Regarding claims 1, 10, 19, and 20, Brovc et al. teaches the concentration for chemical chelators in antibody formulations. Brovc et al. points to a narrowed range of “the general order of addition was as follows (in brackets are final concentrations): CCA (100 µM); chelating agent or antioxidant (EDTA, DTPA; GSH, quercetin) (10 µM)”, see page 441.
The invention claimed is an antibody aqueous liquid solution composition comprising numerous well-known components. Shapiro teaches that the antibody comprising SEQ ID NO: 1 and 2 is a known pan-anti-TGF-β antibody that inhibits TGF-β1, TGF-β2, and TGF-β3 ([0104]) and that deregulation of TGF-β leads to cancer ([0003]). The claimed compositions of the antibody aqueous liquid solutions include a range of concentrations of antibody to provide a therapeutically effective amount, as taught by Brisbane, concentration ranges of acetate to provide a stable pH, as taught by Brisbane, concentration ranges of sucrose to further enhance composition stability, as taught by Dubey, concentration ranges of chelating agent to improve antibody stability by chelating metals, as taught by Brisbane, concentration ranges of surfactant to reduce protein aggregation and surface adsorption, as taught by Brisbane, and a range of pH to avoid pH-induced antibody instability, as taught by Shapiro. The combination of the components recited in claim 10 are enumerated as above and recited in claims 1-2, 5-6, 9 and 16-20. The teachings of Brovc provide a narrower, experimentally determined range for the concentration of EDTA and DTPA that would aid in combatting the effects of oxidation in solution. An article of manufacture or a kit is provided for protection against instability of the antibody aqueous liquid solution compositions, as taught by Shapiro. Methods for the treatment of cancer by intravenous administration of therapeutically effective doses of antibody aqueous liquid solution compositions, which may include additional anti-cancer therapies as taught by Shapiro.
In antibody aqueous liquid solution compositions, it would have been prima facie obvious to one of ordinary skill in the art to intravenously administer anti-TGF-β antibody, potentially in conjunction with a second anti-cancer therapy, at therapeutically effective amounts to inhibit TGF-β1, TGF-β2, and TGF-β3 for the treatment of cancer. Furthermore, additional components of antibody aqueous liquid solution compositions, as recited above, would be included to provide compositions with predictable and reasonable expectations of therapeutic success. Methods and components provided, as recited above, would provide guidance for preparation and administration of antibody aqueous liquid solution compositions for the treatment of cancer, which is proper to support a finding of obviousness under 35 U.S.C. 103(a).
Therefore, claims 1-2, 5-6, and 9-20 are rejected.
Response to Arguments
Applicant's arguments filed 06/24/2026 have been fully considered but they are not persuasive.
Applicant argues “the Examiner has in effect used improper hindsight to construct a prima facie case of obviousness against Applicant’s claims” by “cherry-picking various claim amendments for the four references”. This is not found persuasive.
The various references used in the instant rejection teach a variety of antibody formulations with a variety of chemical additions that are routine in the art. Certain references, e.g., Shapiro, teach the instantly claimed antibody and a method of treating cancer in a patient with said antibody, while others like Brisbane teach the necessary additions to the liquid formulation that aid in its stability and longevity. The aspects of the references that the Examiner pulls out for the rejection are relevant to the instantly claimed antibody because they read on the instant claim limitations and the references explain the rationale behind the addition of each of them. In regards to antibody formulations, one of ordinary skill in the art would recognize that certain components, such as sugars and chelating agents, are routinely included in formulations, while the amounts and concentrations of such are experimentally determined according to the identity of the antibody. The optimization of a pharmaceutical formulation for an antibody (e.g., modification of pH or excipient concentration) is considered routine and conventional within the art, and the argument that modification of the formulation renders the instant formulation distinct from the formulation of the prior art is not persuasive for nonobviousness. It would have been obvious to the ordinary artisan to modify the composition to improve a characteristic like antibody stability because it was already known that such changes could be advantageous when preparing pharmaceutical compositions for antibodies. One of ordinary skill in the art would argue that the stability observed after modification and optimization of the composition was expected, especially in the view of the art recognized need to develop stable antibody formulations and to modify the formulation to provide the best stability for a specific antibody through routine optimization. Modifying the composition to reach this endpoint is a part of routine optimization.
Applicant argues that the Examiner does not explain why they have excluded the addition of “arginine” to the formulation in the instant rejection, since it is taught in the cited prior art but not in the instant claims. This is not found persuasive.
The references used in the rejection have arrived at the same concentrations that are instantly taught, and did so prior to the filing date. The prior art is applied in the rejection of the instant claims by citing what parts of the reference teaches the limitations recited in the instant claims. If a limitation is not listed in the claims, then the rejection does not need to point out the absence of the “negative limitation”. It is unclear how Applicant expects that the Examiner should teach these negative limitation in a rejection if they are not mentioned in the instant claims. Additionally, Applicant’s arguments regarding the Examiner’s use of hindsight reasoning and cherry picking is not persuasive because teachings of the prior art are permitted to teach a broader range than is claimed in addition to various other embodiments of their subject matter. This fact does not avoid a finding of prima facie obviousness in light of the overlap of the claimed range. “Selecting a narrow range from within a somewhat broader range disclosed in a prior art reference is no less obvious than identifying a range that simply overlaps a disclosed range.” In re Peterson, 315 F.3d at 1329—30.
Applicant argues that Brovc further teaches away from the claimed formulations as it teaches that the addition of chelating agents is damaging to proteins. This is not found persuasive.
Applicant points to the Abstract where Brovc discloses that adding chelators to formulations may result in resultant complexes with metals that can be even more damaging and that the addition of chelating agents to the therapeutic protein formulation should be carefully considered. However, Brovc recognizes that this is protein formulation dependent and that “as every formulation is unique, justification for EDTA or DTPA addition should be based on experimental data and not common practice”, see Abstract. As such, one of ordinary skill in the art would take into account whether or not a formulation could handle the addition of a chelating agent before adding such. According to the other references cited in the obviousness rejection which teach similar formulations for the same antibody that is instantly claimed, the experimental data shows that the instantly claimed antibody and formulation would benefit from the addition of a chelating agent. Additionally, Brovc was relied upon to teach the concentration of the chelating agent in the formulation as Brisbane already discloses the need for a chelating agent in the antibody formulation.
In contrast to applicants’ assertions, Brovc’s teachings are not limited to the specific working examples involving chelating agents, but broadly include the contents of the entire disclosure. MPEP § 2123(I) states “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). Furthermore, “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….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Therefore, the claims remain rejected as obvious over Shapiro, Brisbane, Dubey, and Brovc.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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