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 .
Claim Status
Claim listing filed on September 29, 2025 is pending. Claims 1-45, 47-58, 60-105, and 108 are canceled. Claims 46, 59, 106-107, 110-111, and 113 are amended. Claims 116-121 are new. Claims 46, 59, 106-107, and 109-121 are examined upon their merits.
Withdrawn Objections and Rejections
Applicant’s cancelation of Claims 102 and 108 have rendered all previous rejections directed to these claims moot.
Applicant’s amendments to the specification and the claims have overcome all specification objections and claim objections of record. As such, the specification objections and claim objections are withdrawn.
The objection directed to sequence compliance in the drawings is withdrawn in view of Applicant’s remarks filed September 29, 2025. Specifically, MPEP § 2412.04 states that the appropriate SEQ ID NOs can be listed in the Brief Description of the Drawings.
The rejection of claims 46, 59, 106-107, and 109-115 under 35 U.S.C. 112(a) as failing to comply with the written description and enablement requirements is withdrawn in view of Applicant’s amendments. The claims are now directed to a TCR comprising the CDR sequences SEQ ID NOs: 6-11 without variation in amino acid sequences.
The rejection of Claims 109-111 and 115 under 35 U.S.C. 101 as being directed to a nature-based product without significantly more is withdrawn in view of Applicant’s remarks filed September 29, 2025. Applicant argues that the 2014 interim guidance on patent subject matter eligibility nature-based product examples illustrate that any non-natural structure gives rise to the level of a marked difference. Examiner agrees that in Example 7, the example Claim 1 drawn to an isolated naturally-occurring nucleic acid is ineligible under 35 U.S.C. 101, but example Claim 3 drawn to the isolated nucleic acid further comprising a fluorescent label attached to the nucleic acid is eligible under 35 U.S.C. 101. Even though fluorescent labeling is routine in the art, adding the fluorescent label makes the nucleic acid structurally different than its naturally-occurring counterpart. Further, in Myriad, 569 U.S. at 580, 106 USPQ2d at 1974-75, the claimed cDNA had the same functional characteristics as its naturally-occurring counterpart but a different structure, and the Supreme Court identified the claims as eligible under 35 U.S.C. 101 (MPEP § 2106.04(c).II.C.1). In instant claims 109-111, soluble TCRs do not occur in nature. Even though the soluble TCR has the same function as the naturally-occurring TCR, the soluble TCR is structurally different as it is not embedded in the cell membrane. In instant Claim 15, TCRs are not associated with one another via linker molecules or non-naturally occurring disulfide bonds in nature. While T cells can naturally comprise a plurality of TCRs, they are not linked to one another by a linker molecule. Thus, the TCRs of Claim 115 are structurally distinct from their naturally-occurring counterparts.
Claim Rejections - 35 USC § 112 (New, necessitated by amendment)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 119-120 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 119 recites “a therapeutic moiety” and Claim 120 recites “an immunostimulating agent.” These phrases are considered functional language because the feature (the moiety / the agent) is defined by what it does (therapeutic / immunostimulating) rather than by what it is (MPEP § 2173.05(g)). To determine if functional language is ambiguous, the following factors are considered: (1) whether there is a clear cut indication of the scope of the subject matter covered by the claim; (2) whether the language sets forth well-defined boundaries of the invention or only states a problem solved or a result obtained; and (3) whether one of ordinary skill in the art would know from the claim terms what structure or steps are encompassed by the claim. These factors are examples of points to be considered when determining whether language is ambiguous and are not intended to be all inclusive or limiting (MPEP § 2173.05(g)). The specification lists non-limiting examples of therapeutic moieties (paragraphs [0067] and [0072]), but no clear boundaries are provided for the structure encompassed by “therapeutic moiety.” The specification defines “an immunostimulating agent such as an interleukin or a cytokine” (paragraph [0069]) which lists two non-limiting examples and provides no structural boundaries for the claimed agents. The metes about bounds of the therapeutic moieties and immunostimulatory agents cannot be readily determined, and Claims 119-120 are rejected as being indefinite.
Note, “radioactive agent” (Claim 120) is not indefinite because it describes an inherent physical property and not a required function. Note, “a chimeric antigen receptor-signaling tail” (Claim 121) is defined by the specification to comprise the transmembrane domain and the endodomain (paragraph [0080]).
Claims 118-120 are rejected 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. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 118 recites wherein the α chain and β chain regions are each modified to include a non-naturally occurring cysteine residue. Claim 118 is interpreted with the broadest reasonable interpretation that the cysteine mutation can be made anywhere in the α chain and β chain regions, including the variable regions as long as the CDR sequences of Claim 1 are maintained. Claims 119-120 are directed to the TCR further comprising a therapeutic moiety linked to the TCR wherein the therapeutic moiety can comprise any immunostimulating agent, chemotherapeutic, radioactive agent, enzyme, or small molecule cytotoxic agent. It is interpreted that the therapeutic moiety can be linked to the TCR at any location, even the N-terminus of the variable domains. Therefore, the claims are directed to a genus of possible engineered TCRs.
The specification teaches no examples of mutating any residues in the α chain and β chain regions to cysteine residues. Further, the specification teaches no examples of linking a therapeutic moiety to the TCR. Therefore, the specification does not provide adequate written description of the claimed genus of engineered TCRs that have substantial variation in cysteine mutations and therapeutic moiety linkages. Claims 118-120 are rejected for insufficient written description.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 118-120 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The breadth of the claims and nature of the invention:
The nature of the invention is complex. As understood with the broadest reasonable interpretation, Claim 118 encompasses making cysteine mutations anywhere in the α chain and β chain regions, including the variable regions as long as the CDR sequences of Claim 1 are maintained. Claims 119-120 are directed to the TCR further comprising a therapeutic moiety linked to the TCR wherein the therapeutic moiety can comprise any immunostimulating agent, chemotherapeutic, radioactive agent, enzyme, or small molecule cytotoxic agent. It is interpreted that the therapeutic moiety can be linked to the TCR at any location, even the N-terminus of the variable domains. Therefore, the claims are directed to a genus of possible engineered TCRs.
The state of the prior art and level of predictability in the art:
The level of predictability in the art depends, most importantly, on whether the claimed invention can be practiced by one of ordinary skill in the art. In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court stated: “An antibody' s structure does much to dictate its function—its ability to bind to an antigen and, in some instances, to block other molecules in the body from doing the same. Different antibodies have different binding and blocking capacities based on the amino acids that compose them and their three-dimensional shapes.” See id., at 11–12. Despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody' s structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody' s structure and function. Ibid (further Amgen teachings are of record in non-final office action filed 05/06/2025). The unpredictability of amino acid mutations applies to TCRs which comprise antigen-binding CDRs that are analogous to those present in antibodies.
Because changing even one amino acid can alter a polypeptide’s structure and binding function, there is a lack of predictability in mutating any residue in the α chain region and the β chain region to form a non-natural disulfide bond. If the mutations are made in between the CDRs, the inserted disulfide bond could disrupt binding function. Further, adding any type of therapeutic moiety through a linker at any location on the TCR could also disrupt binding function. For example, linking a sterically heavy therapeutic moiety to the N-terminus of the variable regions (nearest the CDRs) is likely to block binding function.
The case law shows a continued lack of predictability even after the effective filing date of the instant invention, and there is no support in the Applicant’s disclosure leading one of ordinary skill to overcome the lack of predictability in the genus of engineered TCRs claimed.
Level of skill in the art:
The level of skill would be high encompassing fusion protein science, immunotherapy, binding assays, etc.
Amount of direction provided by inventor and the existence of working examples:
The specification teaches no examples of mutating any residues in the α chain and β chain regions to cysteine residues. Further, the specification teaches no examples of linking a therapeutic moiety to the TCR. A person having ordinary skill in the art would have to make a substantial inventive contribution in order to make and characterize a representative number of TCR species and screen their characteristics to encompass the claimed genus.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure:
In light of the unpredictability surrounding the claimed subject matter, the undue breadth of the claimed invention’s intended use, and the lack of adequate guidance, one wishing to make and practice the presently claimed invention would be unable to do so without engaging in undue experimentation. Given that structure is essential to function, a person having ordinary skill in the art would have to perform undue further experimentation to make the TCR variants encompassed by the claims (comprising a representative number of cysteine mutations and a representative number of therapeutic moiety linkages) and screen their characteristics in order to practice the invention.
The instant specification does not enable the invention to make and use the genus of engineered TCRs claimed, and Claims 118-120 are rejected.
Claim Rejections - 35 USC § 101 (Maintained)
The rejection of Claims 46, 59, 106-107, 114, and 117 under 35 U.S.C. 101 is maintained because the claimed invention is directed to a nature-based product without significantly more. Note, the rejection of record applied to Claims 46, 59, 106-107, and 114 and now further applies to newly added Claim 117.
Applicant's arguments filed September 29, 2025 have been fully considered but they are not persuasive. Applicant argues that amended Claim 1 recites “the α chain region and β chain region are directly or indirectly covalently bonded” and in a naturally occurring TCR, the α chain region and β chain region are not covalently bonded. This statement is not accurate. Seimiya J. Biochem. 1993 teaches that the T cell receptor α and β chains are covalently linked via a disulfide bond in their extracellular constant regions (abstract). Sadio et al. FEBS Lett. Nov. 2019 teaches that the constant domains of α- and β-chain are naturally connected with a C-terminal disulfide bond (page 478, paragraph 1). Therefore, the naturally-occurring α chain region and β chain region are directly covalently bonded through a disulfide bond between their constant domains. Janeway et al. Garland Science 2001 teaches that there is also a disulfide bond that connects the hinge regions C-terminal of the constant domains (section 3-10 and Fig. 3.12) which teaches that the naturally-occurring α chain region and β chain region are also indirectly covalently bonded through a disulfide bond between their hinge regions. Li et al. Cell. Immun. 1998 teaches that the interchain disulfide bond between TCR chains is required for maintaining the functional integrity of the TCR complex as function was lost when the disulfide bond was disrupted (abstract). Note, the references cited are solely in response to Applicant’s arguments and not as a new grounds of rejection. Therefore, Applicant’s argument that direct or indirect covalent binding between the α and β chain regions is structurally different from naturally-occurring TCRs is not scientifically correct and not persuasive.
Applicant cites the 2014 interim guidance on patent subject matter eligibility nature-based product examples to illustrate that any non-natural structure gives rise to the level of a marked difference. However, the TCRs of Claims 46, 59, 106-107, 114, and 117 are not structurally different than naturally-occurring TCRs as explained above. Note, in regard to Claim 59, naturally-occurring T cells are known to comprise a plurality of TCRs embedded in their cell membranes. In regard to Claim 114, the cell membrane is a lipid bilayer.
Applicant argues that in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, claims directed to a cDNA encoding BRACA1 were held to be patent eligible because the structure was markedly different that the naturally-occurring counterpart (it lacked introns) even though the cDNA was functionally the same and the methods for making the cDNA were routine and conventional. However, this argument does not apply to the instant claims because there is no structural difference between the TCRs of Claims 46, 59, 106-107, 114, and 117 and the naturally-occurring TCRs. Applicant’s arguments are not persuasive, and the rejection is maintained.
Allowable Subject Matter
Claims 109-113, 115-116, and 121 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675