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 .
Election/Restrictions
As previously described, Applicant’s election without traverse of Group I, drawn to a pharmaceutical composition comprising a fusion protein comprising a targeting moiety and an immunomodulatory moiety; kits comprising the pharmaceutical composition; and methods of manufacturing the pharmaceutical composition in the reply filed on 16 February 2026 is acknowledged.
The Examiner notes that Group II claims 189, 193, and 196, have been voluntarily cancelled by the Applicant in response to the Restriction/Election requirement and as such cannot be withdrawn.
Applicant further elects the species of (i) a fusion proteins comprising the anti-EGFR domain VH CDRs 1-3 of SEQ ID NOs: 1, 2, and 3 respectively and VL CDRs 1-3 of SEQ ID NOs: 4, 5, and 6, respectively and the immunomodulatory domain of SEQ ID NO: 23 and (ii) a formulation of concentration of 50mg/ml; a buffer of 10mM citrate phosphate; a tonifying agent of 8% w/v sucrose; and a surfactant of 0.02% w/v polysorbate 80.
Response to Amendment
The amendment filed 13 August 2026 is acknowledged. Applicant has amended claims 162-166, 170, 175, 179, 180-182, 188, 191-192, 197-199. Claims 183-187 and 194-195 are newly cancelled. Claims 200 and 201 are new.
Claim Status
Claims 162-182, 188, 190-192, and 196-201 are pending and under examination in the instant office action.
Withdrawal of Objections
The objection to the drawings is withdrawn in view of the replacement drawings.
Withdrawal of Rejections
The rejection of claims 162-184, 186-188, 190-192, and 194-199 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite is withdrawn in view of the amendments to the claims.
The rejection of claims 162-184, 186-188, 190-192, and 194-199 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in view of the amendments to the claims.
The rejection of claims 162-163, 165-188, 190, and 198-199 under 35 U.S.C. 103 as being unpatentable over U.S. 9988456 to Govindappa et. al. published 5 June 2018 (Of record, IDS dated 2/29/2024) in view of WO2020094122 to Tian et. al. published 14 May 2020 (citations refer to U.S. 20220017601A1 as equivalent English-language disclosure (Of record, IDS dated 2/29/2024)) and Kang, Jichao, X. Lin, and J. Penera. "Rapid formulation development for monoclonal antibodies." BioProcess Int 14.4 (2016): 40-47 is withdrawn in view of the amendments to the claims.
The rejection of Claim(s) 164, 191-192, and 194-197 under 35 U.S.C. 103 as being unpatentable over U.S. 9988456 to Govindappa et. al. published 5 June 2018 (Of record, IDS dated 2/29/2024) in view of WO2020094122 to Tian et. al. published 14 May 2020 (citations refer to U.S. 20220017601 A1 as an equivalent English-language disclosure (Of record, IDS dated 2/29/2024)) Kang, Jichao, X. Lin, and J. Penera. "Rapid formulation development for monoclonal antibodies." BioProcess Int 14.4 (2016): 40-47 as applied to claims 162, above, and further in view of WO2021250275 to Dubey et. al. effectively filed 12 June 2020 is withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 103- New, modifications necessitated by amendment
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.
Claims 162-182, 188, 190-192, and 196-201 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 9988456 to Govindappa et. al. published 5 June 2018 (Of record, IDS dated 2/29/2024) in view of WO2020094122 to Tian et. al. published 14 May 2020 (citations refer to U.S. 20220017601A1 as equivalent English-language disclosure (Of record, IDS dated 2/29/2024)); Kang, Jichao, X. Lin, and J. Penera. "Rapid formulation development for monoclonal antibodies." BioProcess Int 14.4 (2016): 40-47; and WO2021250275 to Dubey et. al. effectively filed 12 June 2020.
Regarding claims 162 and 177, Govindappa et. al. teaches a liquid pharmaceutical composition (Col. 17 lines 11-29) comprising a fusion protein that comprises a targeting moiety and an immunomodulatory moiety wherein the immunomodulatory moiety binds to TGF-β and the targeting moiety binds to EGFR (Col. 4 lines 26-32), wherein the immunomodulatory moiety comprises the amino acid sequence of the TGF-β extracellular domain (Col. 5 lines 12-20). Govindappa et. al. teaches that the TGF-β ECD comprises SEQ ID NO: 12 (Fig. 4) which is 100% identical to instant SEQ ID NO: 23 (reads on claims 162, 185). Govindappa et. al. teaches the fusion protein comprising SEQ ID NO: 28 and SEQ ID NO: 8 (Fig. 14), which are 100% identical to instant SEQ ID NO: 10 and SEQ ID NO: 29, comprising VH and VL CDRs 100% identical to instant CDRs of SEQ ID NOs: 1-3 and 4-6, respectively; comprising a VH and VL 100% identical to instant VH and VL SEQ ID NO: 7 and 8; comprising the TGFB-RII ECD 100% identical to instant SEQ ID NO: 23; comprising targeting moiety heavy chain and light chain identical to instant SEQ ID NO: 10 and 11; and comprising a peptide linker (G4S)3 100% identical to instant SEQ ID NO: 24.
Govindappa et. al. teaches that pharmaceutically acceptable compositions refer to carriers, diluents, excipients and the like that can be administered to a subject and that various pharmaceutical formulations appropriate for administration to a subject are known in the art as described in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Co., Easton, Pa. (1990); and The Merck Index, 12th ed., Merck Publishing Group, Whitehouse, N.J. (1996) (Col. 17 lines 11-41). Govindappa et. al. teaches that the fusion Mabs were adjusted to neutral pH or stable formulation pH after purification (Col. 21 lines 64-Col. 22 line 2).
Regarding claim 188, Govindappa et. al. teaches a method of manufacturing the pharmaceutical composition comprising expressing a polynucleotide encoding the fusion polypeptide in a stable cell line such as a mammalian cell line (Col. 6 line 66-Col. 7 line 5); and additionally, a method a manufacturing comprising purifying the fusion protein from the cell supernatant and adjusting back to the stable formulation pH (Col. 21 line 48-Col. 22 line 2).
Govindappa et. al. does not teach the pharmaceutical composition comprising a citrate phosphate buffer present at a concentration from 5 mM to 30 mM; a tonifying agent present at a concentration from 4%w/v to 10%w/v; and wherein the pharmaceutical composition has a pH from 5.5 to 7.0.
This deficiency is resolved by Tian et. al., Kang et. al., and Dubey et. al.
Tian et. al. teaches a pharmaceutical composition comprising a fusion protein comprising an immunomodulatory domain comprising the TGF-βRII ECD and a targeting domain comprising an anti-PD-L1 antibody, wherein the pharmaceutical composition comprises a buffer from 5mM to 30mM, preferably about 10mM [0022]; a saccharide, most preferably sucrose, from 50mg/mL to 100mg/mL (equivalent to 5% to 10% w/v) [0023-0025]; wherein the pH is from 5.0 to about 7.5, preferably 6.2 [0020] (reads on 6.0+0.3).
Regarding claim 163-166, and 197, Tian et. al. teaches the buffer is selected from a group consisting of a histidine salt buffer, a succinate buffer, a phosphate buffer, and a citrate buffer [0012]. Tian et. al. teaches the buffer at a concentration from 5mM to 20mM, preferably 10mM [0022].
Regarding claims 167-169, Tian et. al. teaches the composition comprises a saccharide and the saccharide is trehalose or sucrose, most preferably sucrose [0023].
Regarding claim 198 and 170-171, Tian et. al. teaches the concentration of the saccharide is most preferably 80mg/mL (reads on 8% w/v) [0024].
Regarding claims 172-176 Tian et. al. teaches the composition comprises a surfactant, preferably polysorbate 80 [0026]. The surfactant is about 0.1mg/mL to 0.8mg/mL (equivalent to 0.01% to 0.08%) [0027].
Regarding claim 178, Tian et. al. teaches the composition may be lyophilized [0060-0064] (reads on powder).
Regarding claims 179-180, Tian et. al. teaches that a stable formulation of the antibody is a preparation wherein no changes are observed when stored at 2-8°C for preferably up to 1 year [0096] and testing for stability under conditions such as 5 cycles of freezing and thawing [0216].
Regarding claim 181 and 182, Tian et. al. teaches the concentration of the fusion protein from about 30 mg/mL to about 70mg/mL [0031] and in particular about 50mg/mL [0033].
Regarding claim 190, Tian et. al. teaches a kit comprising the pharmaceutical composition. Tian et. does not teach the kit comprises instructions for use; as stated in MPEP §2112.01 "Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability….[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate."
Dubey et. al. teaches diluent for diluting a drug product which comprises a hetero-dimeric multispecific immunoglobulin (Abstract). Dubey et. al. teaches that the heterodimeric antibody comprises an anti-EGFR targeting domain, wherein the anti-EGFR targeting domain may comprise the amino acid sequences of SEQ ID NOs: 45 and 46 (which comprise a VH and VL 100% identical to instant SEQ ID NOs: 7 and 8) (p. 25 lines 6-10); wherein the buffer is citrate-phosphate at a pH between 6.0 and 7.0 (See Example 2, p. 35). The citrate-phosphate buffer at pH 6 (Buffer C16) was found to be stable when stored at 5°C for 3 months (p. 52-53). Dubey et. al. teaches that usage of the dual-buffer system citrate-phosphate “dramatically improved the stability of diluents containing Lysine HCl as a stress storage condition”. C16 as a diluent was stable for up to 29 months when stored at 5°C (p. 59-61).
Kang teaches by studying commercial antibody products, they established a rich database for successful antibody formulations (page 40, middle column, second paragraph). Kang teaches although every antibody is unique, the molecules are highly similar structurally (page 40, middle column, second paragraph). Kang teaches lessons learned from successful examples are invaluable in developing stable and effective formulations for new antibody formulations (page 40, middle column, second paragraph). Kang teaches 37 formulations that have been successfully used in commercial antibodies, with 25 as liquid formulations, with their concentration ranging from 2 mg/mL to 200 mg/mL (page 40, middle column, third paragraph). Kang teaches Table 1 lists excipients used in these antibody formulations. Kang teaches some commonalities can be observed: phosphate is present in 33% of formulations (page 40, middle column, second bullet) and 35% of liquid formulation (Table 1, page 42), sucrose was present in 30% of liquid formulations (page 40, right column, first bullet), and 72% of formulations used polysorbate 80 as a surfactant (page 40, middle column, third bullet). Kang teaches formulation development wherein stage one identifies the optimal pH, stage 2 identifies stabilizing excipients, and stage 3 is an in depth evaluation of the most stabilizing buffers and excipients (page 42, left column last paragraph to right column, third bullet). Kang teaches in just a few weeks, researchers can develop a stable formulation for antibody product development (page 45, left column, second paragraph).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to take the pharmaceutical composition for stability of fusion proteins comprising a targeting moiety and the TGF-BRII ECD and optimize it for the fusion protein comprising an anti-EGFR antibody and the TGF-BRII ECD as taught by Govindappa et. al. in order to get a stable formulation as taught by Govindappa, using the citrate-phosphate buffer as taught by Dubey et. al. to increase the stability of heterodimeric antibodies comprising sequences identical to the instant anti-EGFR antibodies; and in the method of obtaining a stable antibody formulation as taught by Kang et. al. This would result in a pharmaceutical composition comprising a fusion protein comprising SEQ ID NOs: 8 and 29 as taught by Govindappa comprising 10mM citrate-phosphate buffer as taught by Dubey et. al.; comprising 50mg/mL of the fusion protein (reads on claims 181, 182, 191, 200, and 201); 80mg/mL sucrose (reads on 8%w/v) (reads on claims 191, 198, 200, 201); and a polysorbate 80 concentration of from 0.1mg/mL to 0.8mg/mL (reads on 0.01% to 0.08% w/v), which overlaps with the instant 0.02% w/v concentration (reads on claims 176, and 199-201) as taught by Tian et. al., at a pH of 6.2 as taught by Dubey et. al. (reads on 6.0+0.3; claims 191, 201) . This would further result in the stability characteristics as recited in claims 179-180 because both Kang et. al. and Tian et. al. teach optimizing for these stability characteristics and that the buffers, tonifying agents, and surfactants are results-effective variables to increase the stability of the fusion protein; using the same compositions in the same ranges for the same fusion protein would naturally result in the same stability characteristics. There is a reasonable expectation of success because:
The fusion protein of Govindappa et. al. has 100% sequence identity to the fusion protein of the instant application; and the fusion protein of Tian et. al. comprises an IgG targeting moiety that comprises an antibody (and would have highly similar structures as taught by Kang) and a TGF-BRII ECD 100% identical to the instant SEQ ID NO: 23. Govindappa et. al. recognized that antibody formulations comprising acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed and known to those skilled in the art. Thus, utilizing known pharmaceutical reagents to produce stable formulations of known antibodies would be optimized for a highly similar fusion protein with the formulations of Tian et. al. and the results would affect the formulation with an expected range;
Dubey et. al. teaches that heterodimeric antibodies comprising 100% identity to the anti-EGFR targeting domains of Govindappa had improved stability in citrate-phosphate buffer between pH 6.0 and 7.0;
Kang recognized that the antibody formulations comprising acceptable carriers, excipients or stabilizers are nontoxic to recipients at the dosages and concentrations employed and other standard ingredients are known to those skilled in the art. Further, Kang taught it is common for commercial antibodies to have a formulation with citrate or phosphate, sucrose, and a surfactant as polysorbate 80 and that citrate has a pKa of 6;
Tian et. al. teaches that a highly similar fusion protein was stable in a formulation of citrate, sucrose, polysorbate 80, at a pH of 6.2.
Regarding claim 188 and 192, it would have been obvious for a person of ordinary skill in the art, before the effective filing date, to perform a method of manufacturing comprising expressing the fusion protein stably in mammalian cells as taught by Govindappa and purifying it from the cell supernatant followed by adjustment back to the stable formulation as taught by Govindappa et. al. in the formulation buffer for increased stability as taught by Govindappa et. al. in view of Tian et. al., Kang et. al., and Dubey et. al. as described above. This would have a predictable effect because a person of ordinary skill in the art would expect to be able to use the general purification protocol and to reconstitute in the formulation buffer that was optimized as generically taught by Govindappa et. al.
Response to Arguments
Applicants’ arguments have been fully considered but are not persuasive.
First, Applicant notes that the rejection of claims 164, 191-192, and 194-197 over Govindappa, Tian, and Kang should be withdrawn because modified Govindappa et. al. does not teach the citrate phosphate buffer required by the amended claims (Remarks 8/13/2026 p. 10-11). This is persuasive and the rejection is withdrawn, but is moot in view of the new rejection, necessitated by amendment, over Govindappa, Tian, Kang, and Dubey as described above.
Applicant argues that a person of ordinary skill in the art would not have been motivated to combine the citrate-phosphate buffer of Dubey et. al. with the formulation as taught by Govindappa et. al., Tian et. al., and Kang et. al. for several reasons (Remarks p. 11-12).
First, applicant argues the rejection does not meet the burden of a prima facie case of obviousness because there is no motivation to combine because the instant protein is directed towards a fusion protein comprising a homodimeric anti-EGFR antibody fused to the extracellular domain of human TGFBRII, while Dubey is solely focused on multispecific heterodimeric antibodies comprising engineered Fc domains that comprised engineered Fc regions, and that “as such the amino acid sequence of any of the VH/VL antibodies described in Dubey would be irrelevant to a person of ordinary skill in the art reading Dubey for teachings related to protein formulations (Remarks p. 12-14). This is not persuasive because all of Govindappa et. al., Tian et. al., Kang et. al., and Dubey et. al. teach formulations for the relative stability of antibodies and proteins. A person of ordinary skill in the art would consider that both variable domains, as well as the Fc domains, of a heterodimeric antibody are important for the overall stability of the antibody. For example, Ionescu, Roxana M., et al. "Contribution of variable domains to the stability of humanized IgG1 monoclonal antibodies." Journal of pharmaceutical sciences 97.4 (2008): 1414-1426 teaches that in examining three humanized IgG1 monoclonal antibodies and their Fab and Fc fragments, the enthalpy was similar for all three Fab fragments, but the apparent melting temperatures of the Fab fragments were found to vary significantly (Abstract) and further that low Fab stability may be problematic for long-term storage or consistency of production (Abstract). Therefore, a person of ordinary skill in the art would reasonably believe that a formulation such as a citrate-phosphate buffer that contributed to the stability of an antibody comprising an identical Fab may reasonably be expected to be a stable formulation for either a heterodimeric antibody or a homodimeric fusion protein comprising that antibody.
Applicant also argues that a person of ordinary skill in the art would not understand the citrate-phosphate buffer of Dubey for the citrate buffer of Tian et. al. because Tian teaches away from using a citrate phosphate buffer by stating “preferred phosphate buffer is disodium hydrogen phosphate-sodium dihydrogen phosphate.” Tian at [0089]” (Remarks p. 14). MPEP §2145 states that “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, although Tian et. al. teaches a distinct preferred phosphate buffer, this is not sufficient to teach away from the citrate phosphate buffer suggested by Dubey et. al. because Tian et. al. teaches a genus of citrate and phosphate buffers are suitable alternate embodiments.
Applicant next argues that there was no reasonable expectation of success at achieving the claimed combination because fusion proteins contain combinations of individual components that do not naturally occur together and that the joining of such disparate components inherently creates unpredictability in producing a stable protein and in maintaining the long-term stability. Further, that because Dubey et. al. teaches heterodimeric multispecific proteins rather than the claimed fusion protein, Kang teaches only monoclonal antibody formulations, and Tian does not teach proteins with highly similar structures as alleged by the Office. Applicant argues that because of these reasons, it cannot be extrapolated with any predictability that the stable protein formulations taught in Tian, Kang, or Dubey can be extrapolated to the claimed fusion protein with any predictability (p. 15-16). This is not persuasive. In regards to the specific formulations of the instant claims, "[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955), and see M.P.E.P. § 2144.05 II.A. It is well settled that "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272,276, 205 USPQ 215, 219 (CCPA 1980). See also Merck & Co. v. Biocraft Labs. Inc., 874 F.2d 804,809, 10 USPQ2d 1843, 1847-48 (Fed. Cir. 1989). This because, as is made clear from the prior art, the determination of the optimal formulation for a known antibody, or antibody-fusion protein is well within the purview of one of ordinary skill in the art at the time the invention was made, and it would have been obvious to one of ordinary skill in the art at the time Applicants' invention was made to determine all operable and optimal intervals of the protein concentration, buffer, tonifying agent, surfactant, etc. because optimal intervals is an art-recognized result-effective variable which would have been routinely determined and optimized in the antibody art. Therefore, it would be conventional and within the skill of the art to identify the optimal formulation to achieve target stability. Further, it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. It would be conventional and within the skill of the art to determine the optimal treatment regimens; and therefore there is a reasonable expectation of success at arriving at the formulation as claimed.
Conclusions
No claims are allowed.
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 Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
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, Gregory Emch can be reached at (571) 272-8149. 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.
/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
Prosecution Insights