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 .
Claims 1-2, 7-8, 11, 15-21 and 24-40 are under consideration
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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.
Rejections Withdrawn
Applicant’s arguments, see Remarks of 01/21/2026 p 1, ¶ 2 – p 5, ¶ 5 regarding the application of the Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) reference have been considered and are persuasive. The priority document for the Chang reference (US 62/677,137) was thoroughly reviewed and TCR-scFv fusion proteins described in the preceding rejection were not mentioned or described in the priority document and, as such, all 35 USC § 103 and NSDP rejections made in view of the Chang reference have been withdrawn.
New Rejections
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 (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.
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.
Claim(s) 1-2, 7-8, 11, 15-21, 24-25 and 31-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) in view of Jakobsen (2014) (Jakobsen, et al., US 2014/0099699 A1; Published 4/10/2014; Priority to 1/3/2012 by way of GB0911566.8, of record).
Chang teaches improved scFvs as well as multispecific binding proteins, pharmaceutical compositions comprising such proteins and therapeutic methods using such proteins and pharmaceutical compositions, including the treatment of cancer (Chang, ¶ 0003). Chang teaches that such multispecific proteins comprise an antigen-binding site that is an scFv linked to a NK cell binding site that is a Fab, wherein the Fab and scFv are linked by a linker (Chang, Abstract):
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Chang also teaches pharmaceutical formulations that contain a therapeutically effective amount of the multi-specific proteins of Chang (Chang, ¶ 0194), including formulations comprising the multi-specific proteins of Chang, mannitol, a phosphate/citrate buffering system, a polysorbate surfactant and water (Chang, ¶ 0199). Chang teaches that the buffer comprises phosphate and citrate and is has a pH between 4 and 8 (Chang, ¶ 0201). Regarding claims 24-25 specifically, Chang teaches that the formulations of Chang comprise therapeutically effective amounts of the proteins of Chang (Chang, ¶ 0194) and are administered in methods of treating cancer that are melanoma (Chang, ¶ 0179-180).
Chang teaches that the proteins in the formulations of Chang comprise aqueous formulations with the protein at 10 mg/mL in combination with a stabilizer that is a sugar, a buffering agent and a surfactant (Chang, ¶ 0205) and also teaches that the surfactant is a polysorbate between 0.1 and 10 mg/mL (Chang, ¶ 0203) and this means that since: 1) Chang teaches a protein concentration of 10 mg/mL and 2) Chang’s surfactant disclosed surfactant concentration between 0.1 and 10 mg/mL, 3) this fully contains the sub-range of surfactant concentration of 7.5 and 10 mg/mL that this amounts to Chang disclosing w/w ratio of surfactant to protein from 0.75:1 to 1:1. Regarding claim 11 specifically, Chang also teaches that the surfactant in the formulations of Chang is polysorbate 20 (Chang, ¶ 0203). Chang also teaches of lyophilized formulations comprising the multi-specific proteins of Chang (Chang, ¶ 0196).
Chang teaches that the formulations of Chang include mannitol that is present at between 5 to 20 mg/mL to act as a tonicifier to stabilize the multi-specific proteins of Chang (Chang, ¶ 0202). Chang also teaches that the lyophilized formulations of Chang further include lyoprotectants that are sucrose (a disaccharide) (Chang, ¶ 0215), with w/w ratios (protein : sucrose) between 1:2 and 1:5 being useful for stabilization of the lyophilized drug product (Chang, ¶ 0216) and this is consistent with the definition of a “stabilizer” in the Specification (Specification, p 4, line 31 – p 5, line 2). Chang also teaches that bulking agents that are mannitol add to the mass of lyophilized mixtures and contribute to the structure of the lyophilized cake (Chang, ¶ 0220). Please note that the mannitol concentrations taught by Chang expressed as a ratio of mannitol to multi-specific protein from 1:2 (5 mg/mLMannitol / 10 mg/mLfusion) to 2:1 (20 mg/mLMannitol / 10 mg/mLfusion) and the surfactant concentrations taught by change expressed as a ratio of polysorbate to multi-specific protein from 0.01 (0.1 mg/mLPolysorbate / 10 mg/mLfusion) to 1 (10 mg/ mLPolysorbate / 10 mg/mLfusion).
Chang does not teach a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8.
Jakobsen teaches on the subject of TCRs binding to the gp100 YLEPGVTA protein and fusions thereof (Jakobsen, Abstract). Jakobsen teaches that Fig. 7 of Jakobsen depicts a non-radioactive cytotoxicity curve showing T cell induced lysis of melanoma cell line Mel526 induced by the anti-gp100 TCR/anti-CD3 scFv taught by Jakobsen (Jakobsen, ¶ 0059; Fig. 7):
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(Jakobsen, Fig. 7).
Please note that Fig. 7 of Jakobsen shows that the % lysis induced approaches a horizontal asymptote of ~ 30% at TCR-scFv concentrations of 10^-10 M and greater. Jakobsen also teaches that the TCR alpha chain of Jakobsen comprises 203 amino acids (Jakobsen, p 41) and the TCR beta chain of Jakobsen comprises 242 amino acids (Jakobsen, p 41-42). Please note that using the average Mw of amino acids of 110 g/mol, this amounts to a Mw of 22,330 g/mol for the alpha chain, a Mw of 26,620 g/mol for the beta chain, for a total Mw of 48,950 g/mol for the TCR component and a total Mw of the TCR-scFv fusion of 76,950 g/mol (28,000 g/mol is the average Mw of an scFv). Multiplying the 10^-10 M concentration (the start of the horizontal dosage asymptote) by 76,950 g/mol amounts to Jakobsen teaching the horizontal dosage asymptote beginning at 7.7 *10^-6 mg/mL TCR-scFv fusion protein.
It would be prima facie obvious to one of ordinary skill in the art formulate the TCR-scFv fusion protein of Jakobsen in the formulations of Chang by starting with the 10 mg/mL multi-specific protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen, the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100-1:1 surfactant: TCR-scFv mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multi-specific protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization. One of ordinary skill in the art would be motivated to do this in order to optimize the formulation parameters taught collectively by Chang and Jakobsen. Chang teaches formulations comprising multi-specific binding proteins at10 mg/mL and Jakobsen teaches that the [TCR-scFv of Jakobsen] vs % melanoma cell lysis curve of Jakobsen approaches a horizontal asymptote approaching ~30% lysis of melanoma cells starting at [TCR-scFv of Jakobsen] at 7.7 *10^-6 mg/mL. This amounts to Chang and Jakobsen collectively teaching a range of 7.7 *10^-6 mg/mL – 10 mg/mL. Also note that statistical techniques such as design of experiments (DoE) and response surface modeling were well-known in the art before the effective filing date of the instant application and are specifically designed for the simultaneous optimization of multiple parameters simultaneously whilst minimizing the number of experiments required. One of ordinary skill in the art would have a reasonable expectation of success starting with the 10 mg/mL protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen, the 1:2 – 2:1 mannitol:protein mass ratio range taught by Chang, the 1:100 - 1:1 surfactant: protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of Jakobsen, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization because: 1) the formulations of Chang were developed for Fab-scFv fusion proteins of Chang, which, like the TCR-scFv fusion protein of Jakobsen, comprises an scFv linked to a soluble antigen-binding immunoglobin fragment linked to an scFv via a linker, 2) all of the final concentrations and ratios of components are within the ranges taught collectively by Chang and Jakobsen, 3) routine optimization is within the purview of one of skill in the art and 4) statistical experimental techniques for simultaneous optimization of multiple components were well-known in the art before the effective filing date of the instant application. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Regarding claim 21 specifically, this also reads on the method of claim 21 because the aqueous formulation must be prepared prior to lyophilization.
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
Claim(s) 1-2, 7-8, 11, 15-21, 24-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) and Jakobsen (2014) (Jakobsen, et al., US 2014/0099699 A1; Published 4/10/2014; Priority to 1/3/2012 by way of GB0911566.8, of record) as applied to claims 1-2, 7-8, 11, 15-21, 24-25 and 31-39 above and in further view of Jakobsen (Jakobsen, et al., WO 2011/001152 A1; Published 1/6/2011, of record).
The teachings of Chang and Jakobsen (2014) are discussed above. In addition, Chang also teaches that the buffer component is between 10 – 200 mM phosphate-citrate buffer (Chang, ¶ 0219).
Chang and Jakobsen (2014) do not teach that the TCR of the TCR-scFv fusion protein of Jakobsen formulated in the formulations of Chang comprises an alpha chain of instant SEQ ID NO: 1 and a beta chain of instant SEQ ID NO: 2 as well as 50 mM pH 6.5 phosphate-citrate buffer.
Jakobsen teaches of TCRs that bind the gp100 YLEGPVTA HLA-2 peptide as well as fusions thereof (Jakobsen, Abstract). Instant SEQ ID NO: 1 is the same as the TCR alpha chain of Jakobsen’s claim 18 (v) and instant SEQ ID NO: 2 is the same as the TCR beta chain of Jakobsen’s claim 18 (viii) (Jakobsen, claim 18). Jakobsen teaches that a preferred embodiment of Jakobsen is the TCR linked with an anti-CD3 scFv (Jakobsen, p 10, ¶ 2). Example 11 of Jakobsen (Jakobsen, p 44 – 47) describes an in vitro assay to test T-cell redirection potency of high affinity gp100/anti-CD3 TCR-scFv fusion protein (Jakobsen, p 44, ¶ 2) wherein Mel526 melanoma cells (Jakobsen, p 44, ¶ 5) were tested vs varying concentrations of several gp100/anti-CD3 TCR-scFv fusion protein (Jakobsen, p 45, ¶ 2) and each fusion was found to have an EC50 between 10-10 and 10-11 M (Jakobsen, p 47, ¶ 2).
It would be prima facie obvious to combine the gp100/anti-CD3 TCR-scFv fusion protein taught by Jakobsen and the formulation parameter ranges collectively taught by Chang and Jakobsen (2014) and arrive at a formulation comprising the TCR-scFv fusion protein of Jakobsen formulated in a formulation comprising a buffer that is 50 mM pH 6.5 phosphate-citrate as well as well as a bulking agent, a stabilizer and a surfactant. One of ordinary skill in the art would be motivated to do this in order to develop an optimized formulation for the TCR-scFv fusion protein of Jakobsen. One would have a reasonable expectation of success using the formulation parameter ranges taught by Chang and Jakobsen (2014) for the scFv-TCR fusion protein of Jakobsen because the formulation parameters of Chang and Jakobsen (2014) are designed for fusion proteins comprising scFvs linked to soluble, antigen-binding immunoglobin fragments and the protein of Jakobsen comprises a scFv linked to a soluble, antigen-binding immunoglobin that is a TCR. One of ordinary skill in the art would have a reasonable expectation of success starting with the buffer concentration and pH ranges taught by Chang and Jakobsen (2014) and arriving at 50 mM phosphate-citrate at pH 6.5 through routine optimization because the claimed values are fully within the ranges taught by Chang and Jakobsen (2014). Additionally, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F. 2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (see MPEP 2144.05). Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
Claim(s) 1-2, 7-8, 11, 15-21, 24-25 and 31-40 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) and Jakobsen (2014) (Jakobsen, et al., US 2014/0099699 A1; Published 4/10/2014; Priority to 1/3/2012 by way of GB0911566.8, of record) as applied to claims 1-2, 7-8, 11, 15-21, 24-25 and 31-39 above and in further view of Addis (Addis, et al., WO 2018/234319; Published 12/27/2018; Priority to 6/20/2017 by way of GB 17098866.6, of record).
The teachings of Chang and Jakobsen (2014) are discussed above. In addition, Chang also teaches that the buffer component is between 10 – 200 mM phosphate-citrate buffer (Chang, ¶ 0219).
Chang and Jakobsen (2014) do not teach that the TCR of the TCR-scFv fusion protein of Jakobsen formulated in the formulation of Chang comprises an alpha chain of instant SEQ ID NO: 3 and a beta chain of instant SEQ ID NO: 4 as well as 50 mM pH 6.5 phosphate-citrate buffer.
Addis teaches of TCRs that bind the HLA-A*02 restricted peptide SLLQHLIGL (derived from germline PRAME antigen) peptide as well as fusions thereof (Addis, Abstract). Instant SEQ ID NO: 3 is the same as the TCR alpha chain of Addis’ SEQ ID NO: 27 (in DAV) and instant SEQ ID NO: 4 is the same as the TCR beta chain of Addis’ SEQ ID NO: 28 (in DAV) and Addis teaches that SEQ ID NOs: 27 and 28 paired together to form the TCR of Addis (Addis, Claim 26). Jakobsen teaches that a preferred embodiment of Jakobsen is the TCR linked with an anti-CD3 scFv (Jakobsen, p 10, ¶ 2).
It would be prima facie obvious to combine the anti-PRAME derivative/anti-CD3 TCR-scFv fusion protein taught by Addis and the formulation parameter ranges collectively taught by Chang and Jakobsen (2014) and arrive at a formulation comprising the TCR-scFv fusion protein of Addis formulated in a formulation comprising a buffer that is 50 mM pH 6.5 phosphate-citrate as well as well as a bulking agent, a stabilizer and a surfactant. One of ordinary skill in the art would be motivated to do this in order to develop an optimized formulation for the TCR-scFv fusion protein of Addis. One would have a reasonable expectation of success using the formulation parameter ranges taught by Chang and Jakobsen (2014) for the scFv-TCR fusion protein of Addis because the formulation parameters of Chang and Jakobsen (2014) are designed for fusion proteins comprising scFvs linked to soluble, antigen-binding immunoglobin fragments and the protein of Addis comprises an scFv linked to an antigen-binding immunoglobin fragment that is a TCR. One of ordinary skill in the art would have a reasonable expectation of success starting with the buffer concentration and pH ranges taught by Chang and Jakobsen (2014) and arriving at 50 mM phosphate-citrate at pH 6.5 through routine optimization because the claimed values are fully within the ranges taught by Chang and Jakobsen (2014). Additionally, in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F. 2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (see MPEP 2144.05). Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
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 1-2, 7-8, 11, 15-21 and 24-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over
claims 1-2 of U.S. Patent No. 10,576,162,
claims 1-6 of U.S. Patent 10,517,960 and
claims 1-22 of US Patent No. 12,134,647
in view of Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) and Jakobsen (2014) (Jakobsen , et al., US 2014/0099699 A1; Published 4/10/2014; Priority to 1/3/2012 by way of GB0911566.8, of record).
Although they are not identical, all of the patented claims are directed to fusion proteins comprising soluble TCRs linked to antibody fragments that are scFvs.
The reference patents do not teach a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the reference patents, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8.
Chang teaches improved scFvs as well as multispecific binding proteins, pharmaceutical compositions comprising such proteins and therapeutic methods using such proteins and pharmaceutical compositions, including the treatment of cancer (Chang, ¶ 0003). Chang teaches that such multispecific proteins comprise an antigen-binding site that is an scFv linked to a NK cell binding site that is a Fab, wherein the Fab and scFv are linked by a linker (Chang, Abstract):
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Chang also teaches pharmaceutical formulations that contain a therapeutically effective amount of the multi-specific proteins of Chang (Chang, ¶ 0194), including formulations comprising the multi-specific proteins of Chang, mannitol, a phosphate/citrate buffering system, a polysorbate surfactant and water (Chang, ¶ 0199). Chang teaches that the buffer comprises phosphate and citrate and is has a pH between 4 and 8 (Chang, ¶ 0201). Regarding claims 24-25 specifically, Chang teaches that the formulations of Chang comprise therapeutically effective amounts of the proteins of Chang (Chang, ¶ 0194) and are administered in methods of treating cancer that are melanoma (Chang, ¶ 0179-180).
Chang teaches that the proteins in the formulations of Chang comprise aqueous formulations with the protein at 10 mg/mL in combination with a stabilizer that is a sugar, a buffering agent and a surfactant (Chang, ¶ 0205) and also teaches that the surfactant is a polysorbate between 0.1 and 10 mg/mL (Chang, ¶ 0203) and this means that since: 1) Chang teaches a protein concentration of 10 mg/mL and 2) Chang’s surfactant disclosed surfactant concentration between 0.1 and 10 mg/mL, 3) this fully contains the sub-range of surfactant concentration of 7.5 and 10 mg/mL that this amounts to Chang disclosing w/w ratio of surfactant to protein from 0.75:1 to 1:1. Regarding claim 11 specifically, Chang also teaches that the surfactant in the formulations of Chang is polysorbate 20 (Chang, ¶ 0203). Chang also teaches of lyophilized formulations comprising the multi-specific proteins of Chang (Chang, ¶ 0196).
Chang teaches that the formulations of Chang include mannitol that is present at between 5 to 20 mg/mL to act as a tonicifier to stabilize the multi-specific proteins of Chang (Chang, ¶ 0202). Chang also teaches that the lyophilized formulations of Chang further include lyoprotectants that are sucrose (a disaccharide) (Chang, ¶ 0215), with w/w ratios (protein : sucrose) between 1:2 and 1:5 being useful for stabilization of the lyophilized drug product (Chang, ¶ 0216) and this is consistent with the definition of a “stabilizer” in the Specification (Specification, p 4, line 31 – p 5, line 2). Chang also teaches that bulking agents that are mannitol add to the mass of lyophilized mixtures and contribute to the structure of the lyophilized cake (Chang, ¶ 0220). Please note that the mannitol concentrations taught by Chang expressed as a ratio of mannitol to multi-specific protein from 1:2 (5 mg/mLMannitol / 10 mg/mLfusion) to 2:1 (20 mg/mLMannitol / 10 mg/mLfusion) and the surfactant concentrations taught by change expressed as a ratio of polysorbate to multi-specific protein from 0.01 (0.1 mg/mLPolysorbate / 10 mg/mLfusion) to 1 (10 mg/ mLPolysorbate / 10 mg/mLfusion).
Jakobsen (2014) teaches on the subject of TCRs binding to the gp100 YLEPGVTA protein and fusions thereof (Jakobsen (2014), Abstract). Jakobsen (2014) teaches that Fig. 7 of Jakobsen (2014) depicts a non-radioactive cytotoxicity curve showing T cell induced lysis of melanoma cell line Mel526 by the anti-gp100 TCR/anti-CD3 scFv of (Jakobsen (2014), ¶ 0059; Fig. 7):
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(Jakobsen (2014), Fig. 7).
Please note that Fig. 7 of Jakobsen (2014) shows that the % lysis induced approaches a horizontal asymptote of ~ 30% at TCR-scFv concentrations of 10^-10 M and greater. Jakobsen (2014) also teaches that the TCR alpha chain of Jakobsen (2014) comprises 203 amino acids (Jakobsen (2014), p 41) and the TCR beta chain of Jakobsen (2014) comprises 242 amino acids (Jakobsen (2014), p 41-42). Please note that using the average Mw of amino acids of 110 g/mol, this amounts to a Mw of 22,330 g/mol for the alpha chain, a Mw of 26,620 g/mol for the beta chain, for a total Mw of 48,950 g/mol for the TCR component and a total Mw of the TCR-scFv fusion of 76,950 g/mol (28,000 g/mol is the average Mw of an scFv). Multiplying the 10^-10 M concentration (the start of the horizontal dosage asymptote) by 76,950 g/mol amounts to Jakobsen (2014) teaching the horizontal dosage asymptote beginning at 7.7 *10^-6 mg/mL TCR-scFv fusion protein.
It would be prima facie obvious to one of ordinary skill in the art to start with the TCR-scFv of the reference patents, the 10 mg/mL fusion protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:protein mass ratio range taught by Chang, the 1:100-1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: TCR-scFv mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the reference patents, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization. One of ordinary skill in the art would be motivated to do this in order to optimize the formulation parameters taught collectively by Chang and Jakobsen (2014). Chang formulations comprising multispecific protein concentrations of 10 mg/mL and Jakobsen (2014) teaches that the [TCR-scFv of Jakobsen] vs % melanoma cell lysis curve of Jakobsen (2014) approaches a horizontal asymptote approaching ~30% lysis of melanoma cells starting at [TCR-scFv] at 7.7 *10^-6 mg/mL. This amounts to Chang and Jakobsen (2014) collectively teaching a range of 7.7 *10^-6 mg/mL – 10 mg/mL protein. Also note that statistical techniques such as design of experiments (DoE) and response surface modeling were well-known in the art before the effective filing date of the instant application and are specifically designed for the simultaneous optimization of multiple parameters simultaneously whilst minimizing the number of experiments required. One of ordinary skill in the art would have a reasonable expectation of success starting with the 10 mg/mL protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100 - 1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the reference patents, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization because: 1) the formulations of Chang were developed for Fab-scFv fusion proteins of Chang, which, like the TCR-scFv fusion proteins of the reference patents, comprises an scFv linked to a soluble antigen-binding immunoglobin fragment linked to an scFv via a linker, 2) all of the final concentrations and ratios of components are within the ranges taught collectively by Chang and Jakobsen (2014), 3) routine optimization is within the purview of one of skill in the art and 4) statistical experimental techniques for simultaneous optimization of multiple components were well-known in the art before the effective filing date of the instant application. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Regarding claim 21 specifically, this also reads on the method of claim 21 because the aqueous formulation must be prepared prior to lyophilization.
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
Claims 1-2, 7-8, 11, 15-21 and 24-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,018,062 in view of Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record).
Although they are not identical, the claims of the ‘062 patent are directed to TCR-scFv fusion proteins (patented claims 1 and 10). Regarding claims 24-25, patented claims 19-21 are directed to methods of treating cancer that is melanoma comprising administering the TCR-scFv fusion proteins of the ‘062 patent to a patient in such need.
The ’062 patent does not teach a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the ‘062 patent, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8.
Chang teaches improved scFvs as well as multispecific binding proteins, pharmaceutical compositions comprising such proteins and therapeutic methods using such proteins and pharmaceutical compositions, including the treatment of cancer (Chang, ¶ 0003). Chang teaches that such multispecific proteins comprise an antigen-binding site that is an scFv linked to a NK cell binding site that is a Fab, wherein the Fab and scFv are linked by a linker (Chang, Abstract):
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Chang also teaches pharmaceutical formulations that contain a therapeutically effective amount of the multi-specific proteins of Chang (Chang, ¶ 0194), including formulations comprising the multi-specific proteins of Chang, mannitol, a phosphate/citrate buffering system, a polysorbate surfactant and water (Chang, ¶ 0199). Chang teaches that the buffer comprises phosphate and citrate and is has a pH between 4 and 8 (Chang, ¶ 0201). Regarding claims 24-25 specifically, Chang teaches that the formulations of Chang comprise therapeutically effective amounts of the proteins of Chang (Chang, ¶ 0194) and are administered in methods of treating cancer that are melanoma (Chang, ¶ 0179-180).
Chang teaches that the proteins in the formulations of Chang comprise aqueous formulations with the protein at 10 mg/mL in combination with a stabilizer that is a sugar, a buffering agent and a surfactant (Chang, ¶ 0205) and also teaches that the surfactant is a polysorbate between 0.1 and 10 mg/mL (Chang, ¶ 0203) and this means that since: 1) Chang teaches a protein concentration of 10 mg/mL and 2) Chang’s surfactant disclosed surfactant concentration between 0.1 and 10 mg/mL, 3) this fully contains the sub-range of surfactant concentration of 7.5 and 10 mg/mL that this amounts to Chang disclosing w/w ratio of surfactant to protein from 0.75:1 to 1:1. Regarding claim 11 specifically, Chang also teaches that the surfactant in the formulations of Chang is polysorbate 20 (Chang, ¶ 0203). Chang also teaches of lyophilized formulations comprising the multi-specific proteins of Chang (Chang, ¶ 0196).
Chang teaches that the formulations of Chang include mannitol that is present at between 5 to 20 mg/mL to act as a tonicifier to stabilize the multi-specific proteins of Chang (Chang, ¶ 0202). Chang also teaches that the lyophilized formulations of Chang further include lyoprotectants that are sucrose (a disaccharide) (Chang, ¶ 0215), with w/w ratios (protein : sucrose) between 1:2 and 1:5 being useful for stabilization of the lyophilized drug product (Chang, ¶ 0216) and this is consistent with the definition of a “stabilizer” in the Specification (Specification, p 4, line 31 – p 5, line 2). Chang also teaches that bulking agents that are mannitol add to the mass of lyophilized mixtures and contribute to the structure of the lyophilized cake (Chang, ¶ 0220). Please note that the mannitol concentrations taught by Chang expressed as a ratio of mannitol to multi-specific protein from 1:2 (5 mg/mLMannitol / 10 mg/mLfusion) to 2:1 (20 mg/mLMannitol / 10 mg/mLfusion) and the surfactant concentrations taught by change expressed as a ratio of polysorbate to multi-specific protein from 0.01 (0.1 mg/mLPolysorbate / 10 mg/mLfusion) to 1 (10 mg/ mLPolysorbate / 10 mg/mLfusion).
Jakobsen (2014) teaches on the subject of TCRs binding to the gp100 YLEPGVTA protein and fusions thereof (Jakobsen (2014), Abstract). Jakobsen (2014) teaches that Fig. 7 of Jakobsen (2014) depicts a non-radioactive cytotoxicity curve showing T cell induced lysis of melanoma cell line Mel526 by the anti-gp100 TCR/anti-CD3 scFv of (Jakobsen (2014), ¶ 0059; Fig. 7):
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(Jakobsen (2014), Fig. 7).
Please note that Fig. 7 of Jakobsen (2014) shows that the % lysis induced approaches a horizontal asymptote of ~ 30% at TCR-scFv concentrations of 10^-10 M and greater. Jakobsen (2014) also teaches that the TCR alpha chain of Jakobsen (2014) comprises 203 amino acids (Jakobsen (2014), p 41) and the TCR beta chain of Jakobsen (2014) comprises 242 amino acids (Jakobsen (2014), p 41-42). Please note that using the average Mw of amino acids of 110 g/mol, this amounts to a Mw of 22,330 g/mol for the alpha chain, a Mw of 26,620 g/mol for the beta chain, for a total Mw of 48,950 g/mol for the TCR component and a total Mw of the TCR-scFv fusion of 76,950 g/mol (28,000 g/mol is the average Mw of an scFv). Multiplying the 10^-10 M concentration (the start of the horizontal dosage asymptote) by 76,950 g/mol amounts to Jakobsen (2014) teaching the horizontal dosage asymptote beginning at 7.7 *10^-6 mg/mL TCR-scFv fusion protein.
It would be prima facie obvious to one of ordinary skill in the art to start with the TCR-scFv of the ‘062 patent, the 10 mg/mL protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100-1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the ‘062 patent, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization. One of ordinary skill in the art would be motivated to do this in order to optimize the formulation parameters taught collectively by Chang and Jakobsen (2014). Chang teaches protein concentrations of 10 mg/mL and Jakobsen (2014) teaches that the [TCR-scFv] vs % melanoma cell lysis curve of Jakobsen (2014) approaches a horizontal asymptote approaching ~30% lysis of melanoma cells starting at [TCR-scFv of Jakobsen] at 7.7 *10^-6 mg/mL. This amounts to Chang and Jakobsen (2014) collectively teaching a range of 7.7 *10^-6 mg/mL – 10 mg/mL concentrations for their respective fusion proteins. Also note that statistical techniques such as design of experiments (DoE) and response surface modeling were well-known in the art before the effective filing date of the instant application and are specifically designed for the simultaneous optimization of multiple parameters simultaneously whilst minimizing the number of experiments required. One of ordinary skill in the art would have a reasonable expectation of success starting with the 10 mg/mL protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100 - 1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the ‘062 patent, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization because: 1) the formulations of Chang were developed for Fab-scFv fusion proteins of Chang, which, like the TCR-scFv fusion protein of Jakobsen, comprises an scFv linked to a soluble antigen-binding immunoglobin fragment linked to an scFv via a linker, 2) all of the final concentrations and ratios of components are within the ranges taught collectively by Chang and Jakobsen (2014), 3) routine optimization is within the purview of one of skill in the art and 4) statistical experimental techniques for simultaneous optimization of multiple components were well-known in the art before the effective filing date of the instant application. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Regarding claim 21 specifically, this also reads on the method of claim 21 because the aqueous formulation must be prepared prior to lyophilization.
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
Claims 1-2, 7-8, 11, 15-21 and 24-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,827,688 in view of Chang (Chang, et al., WO 2019/231920 A1; Published 12/05/2019; Priority to 3/28/2018 by way of US 62/677,137, of record) and Jakobsen (2014) (Jakobsen , et al., US 2014/0099699 A1; Published 4/10/2014; Priority to 1/3/2012 by way of GB0911566.8, of record).
Although they are not identical the patented claims are directed to a method of treating cancer requiring the use of a TCR-scFv fusion protein that is the same as the TCR-fusion protein of the instant application. Regarding the sequence limitations of claim 26, patented 13 is directed to a TCR comprising an alpha chain of patented SEQ ID NO: 4 (same as instant SEQ ID NO: 1) and a beta chain of patented SEQ ID NO: 5 (same as instant SEQ ID NO: 2). Regarding claims 24-25, patented claim 11 is directed to a method of treating melanoma comprising administration of the TCR-scFv fusion protein of the ‘688 patent to a patient in such need.
The ’688 patent does not teach a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8.
Chang teaches improved scFvs as well as multispecific binding proteins, pharmaceutical compositions comprising such proteins and therapeutic methods using such proteins and pharmaceutical compositions, including the treatment of cancer (Chang, ¶ 0003). Chang teaches that such multispecific proteins comprise an antigen-binding site that is an scFv linked to a NK cell binding site that is a Fab, wherein the Fab and scFv are linked by a linker (Chang, Abstract):
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Chang also teaches pharmaceutical formulations that contain a therapeutically effective amount of the multi-specific proteins of Chang (Chang, ¶ 0194), including formulations comprising the multi-specific proteins of Chang, mannitol, a phosphate/citrate buffering system, a polysorbate surfactant and water (Chang, ¶ 0199). Chang teaches that the buffer comprises phosphate and citrate and is has a pH between 4 and 8 (Chang, ¶ 0201). Regarding claims 24-25 specifically, Chang teaches that the formulations of Chang comprise therapeutically effective amounts of the proteins of Chang (Chang, ¶ 0194) and are administered in methods of treating cancer that are melanoma (Chang, ¶ 0179-180).
Chang teaches that the proteins in the formulations of Chang comprise aqueous formulations with the protein at 10 mg/mL in combination with a stabilizer that is a sugar, a buffering agent and a surfactant (Chang, ¶ 0205) and also teaches that the surfactant is a polysorbate between 0.1 and 10 mg/mL (Chang, ¶ 0203) and this means that since: 1) Chang teaches a protein concentration of 10 mg/mL and 2) Chang’s surfactant disclosed surfactant concentration between 0.1 and 10 mg/mL, 3) this fully contains the sub-range of surfactant concentration of 7.5 and 10 mg/mL that this amounts to Chang disclosing w/w ratio of surfactant to protein from 0.75:1 to 1:1. Regarding claim 11 specifically, Chang also teaches that the surfactant in the formulations of Chang is polysorbate 20 (Chang, ¶ 0203). Chang also teaches of lyophilized formulations comprising the multi-specific proteins of Chang (Chang, ¶ 0196).
Chang teaches that the formulations of Chang include mannitol that is present at between 5 to 20 mg/mL to act as a tonicifier to stabilize the multi-specific proteins of Chang (Chang, ¶ 0202). Chang also teaches that the lyophilized formulations of Chang further include lyoprotectants that are sucrose (a disaccharide) (Chang, ¶ 0215), with w/w ratios (protein : sucrose) between 1:2 and 1:5 being useful for stabilization of the lyophilized drug product (Chang, ¶ 0216) and this is consistent with the definition of a “stabilizer” in the Specification (Specification, p 4, line 31 – p 5, line 2). Chang also teaches that bulking agents that are mannitol add to the mass of lyophilized mixtures and contribute to the structure of the lyophilized cake (Chang, ¶ 0220). Please note that the mannitol concentrations taught by Chang expressed as a ratio of mannitol to multi-specific protein from 1:2 (5 mg/mLMannitol / 10 mg/mLfusion) to 2:1 (20 mg/mLMannitol / 10 mg/mLfusion) and the surfactant concentrations taught by change expressed as a ratio of polysorbate to multi-specific protein from 0.01 (0.1 mg/mLPolysorbate / 10 mg/mLfusion) to 1 (10 mg/ mLPolysorbate / 10 mg/mLfusion) and with a pH of 6.8.
Jakobsen (2014) teaches on the subject of TCRs binding to the gp100 YLEPGVTA protein and fusions thereof (Jakobsen (2014), Abstract). Jakobsen (2014) teaches that Fig. 7 of Jakobsen (2014) depicts a non-radioactive cytotoxicity curve showing T cell induced lysis of melanoma cell line Mel526 by the anti-gp100 TCR/anti-CD3 scFv of (Jakobsen (2014), ¶ 0059; Fig. 7):
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(Jakobsen (2014), Fig. 7).
Please note that Fig. 7 of Jakobsen (2014) shows that the % lysis induced approaches a horizontal asymptote of ~ 30% at TCR-scFv concentrations of 10^-10 M and greater. Jakobsen (2014) also teaches that the TCR alpha chain of Jakobsen (2014) comprises 203 amino acids (Jakobsen (2014), p 41) and the TCR beta chain of Jakobsen (2014) comprises 242 amino acids (Jakobsen (2014), p 41-42). Please note that using the average Mw of amino acids of 110 g/mol, this amounts to a Mw of 22,330 g/mol for the alpha chain, a Mw of 26,620 g/mol for the beta chain, for a total Mw of 48,950 g/mol for the TCR component and a total Mw of the TCR-scFv fusion of 76,950 g/mol (28,000 g/mol is the average Mw of an scFv). Multiplying the 10^-10 M concentration (the start of the horizontal dosage asymptote) by 76,950 g/mol amounts to Jakobsen (2014) teaching the horizontal dosage asymptote beginning at 7.7 *10^-6 mg/mL TCR-scFv fusion protein.
It would be prima facie obvious to one of ordinary skill in the art to start with the TCR-scFv of the ‘688 patent, the 10 mg/mL protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100-1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the ‘688 patent, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization. One of ordinary skill in the art would be motivated to do this in order to optimize the formulation parameters taught collectively by Chang and Jakobsen (2014). Chang teaches protein concentration of 10 mg/mL and Jakobsen (2014) teaches that the [TCR-scFv] vs % melanoma cell lysis curve of Jakobsen (2014) approaches a horizontal asymptote approaching ~30% lysis of melanoma cells starting at [TCR-scFv] at 7.7 *10^-6 mg/mL. This amounts to Chang and Jakobsen (2014) collectively teaching a range of 7.7 *10^-6 mg/mL – 10 mg/mL TCR-scFv fusion protein. Also note that statistical techniques such as design of experiments (DoE) and response surface modeling were well-known in the art before the effective filing date of the instant application and are specifically designed for the simultaneous optimization of multiple parameters simultaneously whilst minimizing the number of experiments required. One of ordinary skill in the art would have a reasonable expectation of success starting with the 10 mg/mL multispecific binding protein concentration taught by Chang, the horizontal dosage asymptote starting at 7.7 *10^-6 mg/mL TCR-scFv fusion protein taught by Jakobsen (2014), the 1:2 – 2:1 mannitol:fusion mass ratio range taught by Chang, the 1:100 - 1:1 surfactant: multispecific binding protein mass ratio range taught by Chang and the 1:5 – 1:2 sucrose: multispecific binding protein mass ratio range taught by Chang and the pH range of 4-8 taught by Chang and arrive at a specific formulation comprising: 1) 0.2 mg/mL TCR-scFv fusion protein of the ‘688 patent, 2) 0.5 mg/mL sucrose stabilizer (same as 5% w/v), 3) 0.1 mg/mL mannitol bulking agent (same as 1% w/v) and 4) 0.002 mg/mL polysorbate surfactant (same as 0.02%) and at a pH of 6.8 via routine optimization because: 1) the formulations of Chang were developed for Fab-scFv fusion proteins of Chang, which, like the TCR-scFv fusion protein of Jakobsen, comprises an scFv linked to a soluble antigen-binding immunoglobin fragment linked to an scFv via a linker, 2) all of the final concentrations and ratios of components are within the ranges taught collectively by Chang and Jakobsen (2014), 3) routine optimization is within the purview of one of skill in the art and 4) statistical experimental techniques for simultaneous optimization of multiple components were well-known in the art before the effective filing date of the instant application. Further with respect to optimal dosing regimens, it is not inventive to discover such regimens by routine experimentation when general conditions of a claim are disclosed in the prior art. See in re Aller, 220 F.2d 545, 456, 105 USPQ 233, 235 (CCPA 1955) (see MPEP 2144.05(11)).
Regarding claim 21 specifically, this also reads on the method of claim 21 because the aqueous formulation must be prepared prior to lyophilization.
Response to Arguments
Applicant’s arguments, filed 01/21/2026, dealt entirely with the art rejections of the Office Action of 10/21/2025, which have been withdrawn and do not apply to the current rejection.
Conclusion
Claims 1-2, 7-8, 11, 15-21 and 24-40 are rejected.
No claims are allowed.
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/SYDNEY VAN DRUFF/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643