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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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
Claims 1, 10, 16, and 19 have been amended.
Claims 2 and 8 have been cancelled.
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 (in instant PTO-892).
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.
PNG
media_image1.png
713
758
media_image1.png
Greyscale
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.
PNG
media_image2.png
497
841
media_image2.png
Greyscale
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 01/21/2026 have been fully considered but they are not persuasive.
Applicant argues that the “combination of prior art assumes that stability findings for unrelated antibodies in Brisbane and Dubey can be directly extrapolated to anti-TGFβ antibodies without modifications” and that the prior art does not show that “buffer identity and pH range have a profound, Ab1-specific impact on particle formation and opalescence”. This is not found persuasive.
The teachings of Brisbane and Dubey were relied upon to teach components of the formulation, such as pH, addition of chemical chelators, sucrose concentrations, buffers, etc. One of ordinary skill in the art would recognize that these factors are provided within ranges so that they can be adjusted to the antibody of interest, which in the instant case is taught by Shapiro et al. While the teachings of Brisbane and Dubey do not recite the instantly claimed antibody, one of ordinary skill in the art could adjust the concentration of the various components to reach desired characteristics depending upon the identity of the antibody, such as low turbidity (as evidenced by the selection of an acetate buffer in the prior art). While Shapiro et al. provides a larger range for the pH, Brisbane et al. narrows the range down while also teaching other components of the formulation. 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 et al. 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]). Since the instantly claimed values fall within the ranges set forth by the prior art, one of ordinary skill in the art could use the ranges taught by the prior art as a reasonable starting point to determine the optimal ranges for specific antibodies. Therefore, arriving at the values recited in the instant claims could have been routine experimented for and thus reasonably predicted.
Applicant argues that Dubey teaches the concentration of sucrose in low-concentration antibody formulations, and not a suitable sucrose concentration for a high concentration antibody formulation. This is not found persuasive.
Dubey teaches a broader range for sucrose, encompassing 5-15% concentration, so that a skilled artisan can scale the concentration of the sucrose according to the amount of protein (e.g. antibody) in formulation. The teachings of Dubey et al. recite 5% w/v sucrose for lower concentration antibodies through their working examples; however, one of ordinary skill in the art recognizes that this amount is subject to change within the taught range. It is well known in the art that the amount of sucrose added to an antibody formulation depends on the specific requirements of the formulation and the stability needs of the antibody. As such, one of ordinary skill could experimentally determine the optimal concentration from the supplied range dependent upon the concentration of the antibody of interest.
Applicant is reminded that teachings of the prior art are permitted to teach a broader range than is claimed. 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 Brisbane teaches EDTA at a broad range of 0.02-0.2 mM (20-200 micromolar) and that the newly amended claims recite a narrower range than is taught by the prior art, which have unexpected plateaus in its protective effect that are not predictable. This is not found persuasive.
The obviousness rejection has now been modified in light of the amended claims to introduce a new reference, Brovc et al. 2020, which recites the newly recited limitation of 10 mM of EDTA or DTPA in antibody formulations and the benefits of such. Therefore, this argument is now considered moot.
Applicant argues that the prior art does not provide a reasonable expectation of success. This is not found persuasive.
Applicant argues that antibody formulation is unpredictable and the art expressly recognizes that a particular formulation or excipient that has been shown to stabilize a particular antibody may not stabilize a different antibody. This argument is not persuasive because 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 antibody stability and/or decrease turbidity because it was already known that such changes could be advantageous when preparing pharmaceutical compositions for the specifically recited 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.
Additionally, there is sufficient teaching and guidance in the prior art at the time of filing for one of ordinary skill in the art to experimentally arrive at the claimed values from the ranges taught by the prior art. The limitations recited in the instant claims are predictable because the art teaches the rationale behind each addition to the formulation, which a skilled artisan can adjust depending upon the structure and identity of a particular antibody. The prior art teaches ranges for each of the additions to the formulations, which encapsulates the fact that the art recognizes that there needs to be adjustments made to formulations to adapt to the unique requirements of specific antibodies based on amino acid compositions. The prior art disclosures themselves speak to the fact that formulations are not static and depend on multiple factors to achieve the conditions a specific protein requires to be stable in an aqueous formulation. As such, certain endpoints, such as turbidity, could be routine experimented for and determined based on the existing guidance within the prior art.
The instant claims are drawn to a composition and as such, the combination of references from the prior art address each of the components of the composition and render it obvious. The prior art describes broader ranges for the components of the formulation, and a skilled artisan can experiment to obtain certain values dependent upon their end target.
Applicant argues that the instant formulation has synergistic effects and unexpected stability across stress conditions. This is not found persuasive.
The evidence of unexpected results must be commensurate in scope with the claimed invention (see MPEP §716.02(d)). There is no unexpected result since the prior art already taught that the individual components of the formulation had similar effects and one would expect that combining both of the teachings would produce a better formulation, as shown in Marshal. Please see MPEP 7106.0 (a), I, which states that “a greater than additive effect is not necessarily sufficient to overcome a prima facie case of obviousness because such an effect can either be expected or unexpected. Applicants must further show that the results were greater than those which would have been expected from the prior art to an unobvious extent, and that the results are of a significant, practical advantage. Ex parte The NutraSweet Co., 19 USPQ2d 1586 (Bd. Pat. App. & Inter. 1991) (Evidence showing greater than additive sweetness resulting from the claimed mixture of saccharin and L-aspartyl-L-phenylalanine was not sufficient to outweigh the evidence of obviousness because the teachings of the prior art lead to a general expectation of greater than additive sweetening effects when using mixtures of synthetic sweeteners.).“ The evidence provided by Applicant of unexpected results falls into the additive sweetness combination example and does not show a greater than expected outcome and therefore, the instant invention is obvious over the combination of references.
Therefore, the obviousness rejection is maintained over claims 1-2, 5-6, and 9-20.
Conclusion
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675