Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed Jul. 24, 2026.
Claim Status
Claims 1 and 4-12 are currently pending.
Election/Restrictions
Applicant has elected the invention of Group I, claim(s) 1, 7, and 11-12, drawn to a CD4+ or CD8+ TCR-T cell recognizing a tumor antigen, and a method of using said TCR-T cell in a method of treating a cancer patient. Applicant has elected the species wherein the alternative T cell marker, is a CD8 T cell expressing CXCL13 and TNFRSF18. Claims 4-6 and 8-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected subject matter, there being no allowable generic or linking claim. Claims 1, 7, and 11-12 are considered herein on the merits.
Status of Rejections
Status of the rejections: the previous claim rejections under 35 USC 101, 112(b), 102 and 103 are withdrawn in view of the claim amendments. The previous claim rejections under 35 USC 112(a) are withdrawn in view of the claim amendments and the Declaration of Liu filed 7/24/26 (“Decl. of Liu”) except as specifically maintained below.
Claim Rejections - 35 USC § 112(a), (new)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
2. Claim 12 is 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 12 is directed to methods of treating a tumor in a subject, the method comprising the step of administering to the subject a composition comprising a therapeutic amount of TCR-T cells expressing a TCR that recognizes a tumor antigen.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage expressing a TCR that recognizes an enormously vast genus of about 1x10^52 and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences administered via a first administration route (e.g. subcutaneously, that is necessarily and predictably able to treat colorectal, lung, ovarian, renal, liver or gastric solid tumors in an enormous genus of about 7x10^3 mouse and non-mouse subjects.
The claims are broad for reasonably encompassing an enormous genus of mammalian and non-mammalian subjects.
The claims are broad for encompassing at least 7,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021) that can have melanoma, ovarian, renal, liver, gastric solid tumors, such as mammals, birds, fish, and some amphibians and reptiles, wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), such as (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
The specification teaches only intravenous administration of TCR-T cells to a mouse subject with a tumor (e.g. [0035]).
Those of ordinary skill in the art would immediately recognize the instant claim is far broader in scope than Applicant’s example of a mouse subject.
The claimed methods are recited at a high level of generality for the multitude of anatomically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, alimentary, ingestion, inhalation, mucosal, respiration, intranasal, intubation, intrapulmonary, intrapulmonary instillation, buccal, sublingual, otopically, transdermally, dermal, intradermal, subcutaneously, parenterally, transmucosally, rectally, intracavity, intraglandular, intra-pleurally, intraperitoneally, intravenously, intrarterial, intravascular, intramuscularly, intracranially, intra-spinal, intrathecal, iontophoretic, intraocular, ophthalmic, optical, intraorgan, or intralymphatic (e.g. High et al (U.S. 2015/0111955, [0077]).
The specification discloses intravenous administration of TCR-T cells to a mouse subject (e.g. [0035]).
Those of ordinary skill in the art would immediately recognize the instant claim is far broader in scope than Applicant’s example of intravenous administration.
The claimed method is recited at a high level of generality for the TCR-T cell dosage that is to be administered.
The specification discloses an example of intravenous administration of 6x10^6 TCR-T cells to a mouse subject (e.g. [0035]).
Those of ordinary skill in the art would immediately recognize the instant claim is far broader in scope than Applicant’s example of intravenous administration of 6x10^6 TCR-T cells.
The claim is enormously broad for reciting a genus of TCR-T cells expressing a TCR that recognizes an enormously vast genus of tumor antigens, recited at a high level of generality.
Blair et al (U.S. 2024/0067985) is considered relevant prior art for having disclosed wherein the antigen may be as many as 8 to 35 amino acids in length (e.g. [0022]), or as many as 40 amino acids in length (e.g. [0023]).
20^35 = 3x10^45 structurally undisclosed peptides.
20^40 = 1x10^52 structurally undisclosed peptides.
(www.calculator.net/exponent-calculaton last visited June 25, 2025)
Thus, instant claims reasonably encompass an enormously vast genus of about 1x10^52, and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences that are to be bound by the TCR expressed by the TCR-T cells, respectively.
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
Amgen, Inc., v. Sanofi 872 F.3d 1367 (2017)
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
Accordingly, this limited information is not deemed sufficient to reasonably convey to one skilled in the art that the applicant is in possession of the vast genus of the TCR that recognize every tumor antigen that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment of the recited solid tumor cancer types in an enormous genus of about 1x10^6 human and non-human animal subjects by the genus of any administering.
3. Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, while being enabling for a method of treating a mammalian subject having a tumor comprising the step of intravenously administering over a million TCR-T cells to said subject, does not reasonably provide enablement for the nexus between:
The vast genus of the TCR-T cell dosages expressing a TCR that recognizes an enormously vast genus of about 1x10^52 and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences that is/are to be administered via an enormous genus of anatomically distinct administration routes that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment of the specifically recited solid tumor types in an enormous genus of over about 7x10^3 human and non-human animal subject species.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description, and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention. If not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)). Furthermore, USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage expressing a TCR that recognizes an enormously vast genus of about 1x10^52 and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences administered via a first administration route (e.g. subcutaneously, that is necessarily and predictably able to treat colorectal, lung, ovarian, renal, liver or gastric solid tumors in a diverse genus of about 7x10^3 mouse and non-mouse subjects, including birds and fish.
Maeda et al (Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs, Clinical and Translational Medicine 7: e11, 20 pages, doi.org/10.1186/s40169-018-0185-6; available online March 1, 2018) is considered relevant prior art for having taught that recent immunotherapy for solid tumors (e.g. ovarian cancer) produced outcome failure-rates of 90% (Abstract). Despite the initial enthusiasm for site-specific cancer, the outcomes are bleak and disappointing. Such alarming records of failure of clinical outcomes, the increased publicity for specific vaccines, along with increasing rise of cancer incidence and death created huge and unsustainable cost to the public around the globe. Other recently published articles on basic research and clinical studies of cancer and pathogen-specific vaccines have raised serious concerns about the worthiness, hidden agenda and high costs of these reductionist approaches to such projects that are toxic and repeatedly failed the public (pg. 2, col. 1).
While the isolated molecular entities (e.g. ERV-K-gag, ERV-K-env, hFOLR1) are parts of the highly heterogeneous and chaotic landscape in cancer biology, they should not be considered as ‘target’ for therapy as they have little/no value on their own for translational purposes although they may work in mouse models for the selected conditions and duration of therapy which do not apply to human (e.g. pg. 2, col’s 1-2, joining para).
Targeting genetic mutations in site-specific solid cancers that produced repeatedly failed outcomes while generated huge corporate profits. Molecular target drugs created great business motives for drug industry to focus on them in the last six decades. After revealing extremely high incidence of mutations in solid cancer, very little scientific rationale has been presented for developing such costly molecular target drugs that are based on identification of too many evolving genetic mutations in the chaotic cancer environments (pg. 5, col. 2). Ovarian cancers may comprise as many as 30-60 different mutations (Table 1).
The major concerns on drug screening are safety and therapeutic efficacies, as well as ethical and financial considerations of decision makers who apply the results that are produced in small animal models in clinical trials to test various anticancer agents in patients which repeatedly failed (pg. 10, col. 2).
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of treating a mouse subject having a tumor comprising the step of administering by intravenous injection 6x10^6 TCR-T cells to said mouse, is proper.
Response to Arguments
Applicant’s remarks filed 7/24/26 and Decl. of Liu regarding the previous rejections were found persuasive regarding “effective amount” and “subject,” however applicant’s arguments regarding the universality and predictability over the entire scope of claim 12 was not found persuasive.
As detailed fully above, the instant application does not show possession of the full scope of the genus of TCR that recognizes tumor antigen and that can treat the genus of subjects having solid tumor encompassed by the solid tumor genus of melanoma, colorectal, lung, ovarian, renal, liver, gastric and nasopharyngeal cancers. Similarly, the instant application does not provide sufficient guidance, in view of the prior art, for treatment methods over the full scope of the genus of TCR that recognizes tumor antigen and that can treat the genus of subjects having solid tumor encompassed by the solid tumor genus of melanoma, colorectal, lung, ovarian, renal, liver, gastric and nasopharyngeal cancers unlimited in administering route.
In considering Exhibit A (“Decl. of Liu”), it is noted that post-filing evidence regarding the invention (or predictability of the field) does not apply to the written description rejection as possession is determined at the filing date based on full, clear, concise, and exact disclosure as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention. Regarding enablement, Exhibit A establishes the invention of claim 12 is enabled for human subjects, at least as limited to administering via multiple infusions in combination with IL-2 at quantities of 1-3 million T cells and as to specific but undisclosed antigens (or limited to TCRs specifically binding a similar epitope thereof as those demonstrated due to unpredictability of antigen loss/escape in targeted cancer treatments). Evidence in two mammalian species, humans and immunocompromised mouse models (PDX) does not constitute predictability over the genus of administering and without a minimum or effective amount of cells.
Claim Rejections - 35 USC § 102, (new)
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 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 7, and 11-12 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Schmid (Schmid et al., J Immunol 184: 4936-46 (2010)).
Claim 1 is interpreted as a product-by-process regarding the term “derived” and “introduced into the T cell via a lentiviral vector such that there is no structure/feature implied in the product that would necessarily distinguish the claimed product from one obtained by a different process (e.g., wherein the T cell does not expressing any of the recited markers in the tumor); however, the claim is interpreted as strictly requiring a recombinant structure of some kind, expression of a TCR which recognizes a tumor antigen, and impliying a stably incorporated polynucleotide encoding the TCR.
Regarding claim 1, Schmid discloses a recombinant CD8+ T cell comprising a lentiviral vector expressing a TCR (TCR-T cell) which binds a tumor antigen (NY-ESO-1) (pg. 4940, Fig. 5), including wherein the cell stably expressed the introduced TCR transgene (pg. 4942). These cells were capable of killing tumor cells (melanoma and lymphoblastoid T2-A2 cells) (Fig. 6, 4; pg. 4942).
Regarding claim 7, as noted for claim 1, these product-by-process limitations do not imply any additional requisite structure regarding the claimed product not expressly recited. Thus, claim 7 is anticipated for the same reasons as for claim 1 set forth fully above.
Regarding claim 11, Schmid discloses the cell is in a buffered aqueous solution (RPMI 1640), which qualifies as a type of pharmaceutical composition.
Regarding claim 12, Schmid discloses using such T cells in a method of treating melanoma in a subject via adoptive cell transfer (pg. 4943, left col., last para.; pg. 4945, left col., last para.).
Thus, Schmid anticipates the claimed invention.
Response to Arguments
Applicant’s remarks filed 7/24/26 regarding the previous rejections were found persuasive, however applicant’s claim amendment necessitated the new grounds of rejection presented above.
Claim Rejections - 35 USC § 103, (new)
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 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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.
5. Claim 12 is rejected under AIA 35 U.S.C. 103 as being unpatentable over Schmid as applied to claim 1 above, and in view of Fernandez-Poma (of record).
Regarding claims 11-12, while Schmid suggests claim 11, Schmid does not teach formulating CD8+ TCR T cells in a pharmaceutical composition specifically for administering the composition to a subject bearing a melanoma tumor as a treatment. However, Fernandez-Poma et al is considered relevant prior art for having taught an immunotherapy method of treating a tumor in mouse xenograft subjects, the method comprising the step(s) of administering by intravenous injection to said mouse subjects a pharmaceutical composition comprising 2 x 106 or 107 CD8+ lymphocytes (e.g. pg. 3674, col. 1, Methods, ACT experiments; pg. 3680).
Prior to the effective filing date of the instantly claimed invention, it would have been obvious to one of ordinary skill in the art to arrive at an immunotherapy method of treating a mouse melanoma xenograft subject via a step of administering a pharmaceutical composition comprising CD8+ T cells made by the method taught by Schmid with a reasonable expectation of success of improving at least one aspect in the subject (e.g., tumor load) because those of ordinary skill in the art previously recognized the scientific and technical concepts that administering a pharmaceutical composition comprising CD8+ TCR T tumor-infiltrating lymphocytes to mouse tumor xenograft subjects is feasible and can result in delayed tumor growth, tumor cell depletion, and enhanced survival (Fernandez-Poma et al.).
Response to Arguments
Applicant’s remarks filed 7/24/26 regarding the previous rejections were found persuasive, however applicant’s claim amendment necessitated the new grounds of rejection presented above.
Conclusion
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 ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/
Examiner, Art Unit 1638
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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