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 October 13, 2025 and January 9, 2026.
Amendments
Applicant's amendments, filed October 13, 2025 and January 9, 2026, are acknowledged. Applicant has cancelled Claims 2-3, and amended Claims 5-6 and 8.
Claims 1 and 4-12 are 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.
Within Group I, Applicant has elected the following species, wherein:
i) the alternative T cell marker, is a CD8 T cell expressing CXCL13 and TNFRSF18, as recited in Claims 1 and 7.
Response to Amendments
Applicant argues that the core inventive concept of the present application lies in the identification and screening of markers of T cells that recognize tumor neoantigens, rather than in any specific tumor antigen. Tumor neoantigens are derived from patient-specific gene mutations and thus constitute personalized tumor antigens. The tumor neoantigens vary from patient to patient, and therefore it is not possible to limit the claims to any single specific tumor antigen.
Applicant’s argument has been fully considered. Thus, the tumor antigen species election is withdrawn because each species is considered an obvious variant of the others, and are not considered to be patentably distinct nor the inventive concept of the instant application.
Applicant argues that the steps disclosed in the Group II method (screening tumor antigen-recognizing TCRs / introduction into T cells) and Group III method claims (in vitro antigen stimulation for identification) are not independent inventive concepts unrelated to the TCR-T products and therapeutic uses in Group I.
Applicant’s argument(s) has been fully considered, but is not persuasive. As discussed in the prior Office Action, Groups I-III lack unity of invention a priori because the groups do not share the same or corresponding technical feature. The special technical feature of Group II, not required by Groups I and III, is the step of cloning a TCR and introducing said cloned TCR into a T cell. The special technical feature of Group III, not required by Groups I-II, is the step(s) of performing in vitro tumor antigen stimulation, and identifying the TCR stimulated by said tumor antigen.
Furthermore, Groups I-III lack unity of invention because even though the inventions of these groups require the technical feature of a TCR-T cell that recognizes a tumor antigen, this technical feature is not a special technical feature as it does not make a contribution over the prior art in view of Duhen et al (2018; of record in ISR) who taught CD8+ tumor infiltrating lymphocytes that express HAVCR2 (e.g. pg 2, col. 2). Thus, Claim 1, at least, does not contribute over the prior art.
Applicant argues that Duhen et al is limited to CD8+ TILs expressing CD39 and CD103, but does not disclose the markers of instant Claim 1, including, but not limited to CD4.
Applicant’s argument(s) has been fully considered, but is not persuasive. Instant claim does not require the TCR-T cell to be CD4+. Rather, the claim recites a TCR-T cell derived from any one of the cells in (i) and (ii), including CD8+ T cells expressing HAVCR2, which Duhen et al taught.
Claims 1 and 4-12 are pending.
Claims 4-6 and 8-10 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 7, and 11-12 are under consideration.
Priority
This application is 371 of PCT/CN2021/097813 filed on June 2, 2021.
Acknowledgment is made of Applicant’s claim for foreign priority under 35 U.S.C. 119(a)-(d).
While a certified copy of the foreign patent application China 202010674259.X filed on July 14, 2020 is provided with the instant application, a certified English translation of said foreign patent application has not been provided.
Information Disclosure Statement
Applicant has filed Information Disclosure Statements on February 16, 2023 and October 13, 2025 that have been considered.
The information disclosure statement filed February 16, 2023 and October 13, 2025 fail to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
Bibliographic information provided must be at least enough to identify the publication. author, title and date. For books, minimal information includes the author, title, and date. For periodicals, at least the title of the periodical, the volume number, date, and pages should be given.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
1. Claims 1, 7, and 11 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
With respect to Step 1, the claims are directed to TCR-T cells expressing a TCR that recognizes a tumor antigen, which is a statutory category of invention (Step 1: YES).
With respect to Step 2A, prong one, the judicial exception, the claims are directed to TCR-T cells expressing a TCR that recognizes a tumor antigen, which is a natural product that naturally occurs in, e.g. human patients suffering from cancer, as such is natural law of cell biology and physiology. See, for example, specification [0006]. Thus, the claims are directed to a judicial exception (Step 2A, prong one: YES).
With respect to Step 2A, prong two, the claim does not recite additional elements that integrate the judicial exception into a practical application. While the claims recite a set of TCR-T cell markers, e.g. CD8+, CXCL13+, and/or TNFRSF18, the specification discloses obtaining the TCR-T cells from the subject’s tumor tissue, and using flow sorting of the TCR-T cells using one or more of these markers [0014]. Thus, here too, TCR-T cells expressing the cell markers, e.g. CD8+, CXCL13+, and/or TNFRSF18, is but natural law of cell biology and physiology. The claims do not integrate the judicial exception into a practical application (Step 2A, prong two: NO).
With respect to Step 2B, the inventive concept is the identification of one or more specific TCR-T cell markers that is/are naturally present in a tumor tissue sample from which the ordinary artisan isolates TCR-T cells expressing a TCR that recognizes a tumor antigen. Thus, the claim is not considered to recite additional elements that amount to significantly more than the judicial exception itself (Step 2B: NO).
With respect to Claim 11, directed to a pharmaceutical composition comprising the TCR-T cell, such is recited at a high level of generality, and mere isolation of the TCR-T cells is not considered to recite additional elements that amount to significantly more than the judicial exception itself.
Claim Rejections - 35 USC § 112
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(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.
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(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. Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “patient” in Claim 12 is indefinite because the specification does not clearly redefine the term. While “patient” is commonly used in the art to refer to human patients, the specification discloses a mouse tumor model (e.g. [0030]). Thus, it appears that “patient” encompasses both human and non-human animals.
The Examiner suggests amending the claim to recite “human patient”. Alternatively, if Applicant seeks to encompass non-human animals, then replace “patient” with “subject”.
3. Claim 12 is 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 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.
It is understood that in order to meaningfully treat the subject, and thereby satisfy the requirements of 35 U.S.C. 101 (See MPEP 2107.01 III, Therapeutic or Pharmacological Utility), a therapeutically effective amount or dose of the TCR-T cells expressing an enormously vast genus of structurally undisclosed TCRs recited at a high level of generality that recognize an enormously vast genus of tumor antigens recited at a high level of generality must be administered to the subject, thereby achieving some real-world, clinically meaningful effect, and thereby being of “immediate benefit to the public”.
The phrase “an effective amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In reFredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c)
A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the disease/disorder/condition to be treated [parameter 4]; and
the structure(s) of tumor antigen to be recognized by the TCR-T cells [parameter 5];
the phenotypic response to be achieved [parameter 6].
The phrase “a therapeutic amount”, syn. ‘an effective amount’, denotes that there is an amount of the TCR-T cells expressing a TCR that recognizes a tumor antigen that upon administration to the subject does not, in fact, achieve treatment of a tumor in the subject.
Parameter 1
The claims are broad for reasonably encompassing an enormous genus of human and non-human subjects.
The claims are broad for encompassing about 1,000,000 species of animals (Kingdoms of Life, waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
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 a mouse subject.
Parameter 2
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.
Parameter 3
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.
Parameter 4
The claims are broad for reasonably encompassing an enormous genus of etiologically and pathologically distinct tumors, recited at a high level of generality, including, but not limited to lung cancer, melanoma, intestinal cancer, liver cancer, stomach cancer, breast cancer, cervical cancer, ovarian cancer, kidney cancer, bladder cancer and esophageal cancer [0012].
The Cancer Research Institute (www.cancerresearch.org/blog/exploring-the-different- types-of-cancer-and-treatment-options; December 12, 2023) teaches that there are over 200 different disease types of cancer, each with their own varying subcategories and unique characteristics.
Parameter 5
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.
Parameter 6
The claims are broad for reasonably encompassing an enormous genus of physiologically and phenotypically different results, which evokes the question: A therapeutically effective amount to do what?
The claim does not recite, and the specification fails to disclose, the therapeutic response to be achieved.
If there are multiple ways to measure “therapeutically effective amount”, to wit, TCR-T cell dosage, and/or phenotypic result, yet each yields a different result, then the claim may be indefinite because it is unclear which method is to be performed to determine infringement.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. subcutaneously, that is necessarily and predictably able to eliminate metastatic tumor disease [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. intraperitoneally, that is necessarily and predictably able to reduce tumor size [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], as opposed to a second TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a second administration route [parameter 2], e.g. intravenously, that is necessarily and predictably able to ameliorate a symptom of cancer disease, but not reduce tumor burden [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
See further discussion below in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instant claim(s) as a whole do not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
4. 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 Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejection.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
A “therapeutically effective amount” is a functional property that is dependent upon many different variable parameters, including, but not limited to:
the type of subject human or non-human animal to be treated [parameter 1];
the administration route [parameter 2];
the dosage administered [parameter 3];
the disease/disorder/condition to be treated [parameter 4]; and
the structure(s) of tumor antigen to be recognized by the TCR-T cells [parameter 5];
the phenotypic response to be achieved [parameter 6].
The phrase “a therapeutic amount”, syn. ‘an effective amount’, denotes that there is an amount of the TCR-T cells expressing a TCR that recognizes a tumor antigen that upon administration to the subject does not, in fact, achieve treatment of a tumor in the subject.
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
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)
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. subcutaneously, that is necessarily and predictably able to eliminate metastatic tumor disease [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. intraperitoneally, that is necessarily and predictably able to reduce tumor size [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], as opposed to a second TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a second administration route [parameter 2], e.g. intravenously, that is necessarily and predictably able to ameliorate a symptom of cancer disease, but not reduce tumor burden [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
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).
In the instant case, knowing that the initial TCR-T cell is a CD8+ T cell and expresses CXCL13 and/or TNFRSF18, and a TCR that recognizes a tumor antigen does not tell you anything at all about:
the TCR-T cell dosage [parameter 3] 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 [parameter 5] that is/are to be administered via an enormous genus of anatomically distinct administration routes [parameter 2] that is necessarily and predictably able to achieve a real-world, clinically meaningful treatment [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed claimed method encompasses:
an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1] to be treated;
an enormous genus of anatomically distinct administration routes [parameter 2];
an enormous genus of the TCR-T cell dosages [parameter 3];
an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4];
an enormously vast genus of TCRs that recognize an enormously vast genus of about 1x10^52 and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences [parameter 5];
an enormous genus of therapeutic responses, recited at a high level of generality, to be achieved [parameter 6].
The instant specification discloses administering by intravenous injection 6x10^6 TCR-T cells to a mouse subject suffering from cancer [0035].
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
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-T cell dosages [parameter 3] 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 [parameter 5] that is/are to be administered via an enormous genus of anatomically distinct administration routes [parameter 2] that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1].
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
5. 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 mouse subject having a tumor comprising the step of administering by intravenous injection 6x10^6 TCR-T cells to said mouse, does not reasonably provide enablement for the nexus between:
the vast genus of the TCR-T cell dosages [parameter 3] 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 [parameter 5] that is/are to be administered via an enormous genus of anatomically distinct administration routes [parameter 2] that is/are necessarily and predictably able to achieve a real-world, clinically meaningful treatment [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1].
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 [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. subcutaneously, that is necessarily and predictably able to eliminate metastatic tumor disease [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
The claims fail to recite, and the specification fails to disclose, a first TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a first administration route [parameter 2], e.g. intraperitoneally, that is necessarily and predictably able to reduce tumor size [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], as opposed to a second TCR-T cell dosage [parameter 3] 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 [parameter 5] administered via a second administration route [parameter 2], e.g. intravenously, that is necessarily and predictably able to ameliorate a symptom of cancer disease, but not reduce tumor burden [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1], for example.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
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).
In the instant case, knowing that the initial TCR-T cell is a CD8+ T cell and expresses CXCL13 and/or TNFRSF18, and a TCR that recognizes a tumor antigen does not tell you anything at all about:
the TCR-T cell dosage [parameter 3] 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 [parameter 5] that is/are to be administered via an enormous genus of anatomically distinct administration routes [parameter 2] that is necessarily and predictably able to achieve a real-world, clinically meaningful treatment [parameter 6] of an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4] in an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1].
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that the claimed claimed method encompasses:
an enormous genus of about 1x10^6 human and non-human animal subjects [parameter 1] to be treated;
an enormous genus of anatomically distinct administration routes [parameter 2];
an enormous genus of the TCR-T cell dosages [parameter 3];
an enormous genus of etiologically and pathologically distinct cancers and tumors [parameter 4];
an enormously vast genus of TCRs that recognize an enormously vast genus of about 1x10^52 and/or 3x10^45 structurally and functionally undisclosed tumor antigen amino acid sequences [parameter 5];
an enormous genus of therapeutic responses, recited at a high level of generality, to be achieved [parameter 6].
The instant specification discloses administering by intravenous injection 6x10^6 TCR-T cells to a mouse subject suffering from cancer [0035].
Applicant is essentially requiring the ordinary artisans to discover for themselves that which Applicant fails to disclose.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
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).
The decision makers of such expensive, out-of-focus and fuzzy undertakings seldom consider the life-threatening consequences of wrong and reductionist approaches to drug development for patients and the tremendous economic burden to the society. The irresponsible decision makers of such undertakings, either abandon data on failed outcomes or downplay and ignore the serious consequences of drugs (pg 2, col. 2).
As recently reported, a closer look at cancer science reveals that highly powered structure (hierarchy) in cancer/medical establishment (system) versus antisystem and chaotic approaches to cancer research and therapy (‘medical/scientific ponzi schemes’) are potent recipes for failed therapeutics that kills patients but generates huge corporate profit (pg 4, col. 1). Carrying out such reductionist studies under the different name of immunotherapy present the same narrow views of cancer biology and are far from being effective for cancer patients. In these studies, little considerations are given to the cellular immune composition of site-specific tissues, the immune-non-immune local or systemic compensatory response mechanisms, the bioenergetics and oxido redox profiles of tissues toward checkpoint inhibition, as well as, the host immune and non-immune interactions with recruited cells and the adverse responses that are observed following therapy (pg 4, col. 1).
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).
Prohibitive costs of cancer therapy with repeatedly failed outcomes. Economic impact on medical insurance, and unbearable burden to the society. A serious problem in current cancer chemotherapy involves the cost of care for cancer patients, particularly the astronomical costs of recently claimed molecular ‘targeted’ drug, ‘personalized’ or ‘precision’ medicine with outcome failure rates of 85–95%. While majority of such drugs produced no reasonable benefit to meaningfully extend survival of cancer patients, particularly those with solid tumors, they are tremendously costly for the patients, their families and the public (pg 13).
Concerned voices of independent and competent professionals, oncologists and scientists that are raised for seeking the truth in cancer science, on behalf of the cancer-stricken public for changing the directions in cancer research or therapy or safety and unethical motives behind development of pathogen-specific vaccines (e.g., HPV, flu, meningitis) that repeatedly failed cannot be ignored or silenced any longer by policy/decision makers. We also suggested that the USA policy makers and medical/cancer establishment to return to ‘common sense’ that our forefathers used to serve the public (pg 14, col. 1).
Perrin (Make Mouse Studies Work, Nature (507): 423-425, 2014) taught that the series of clinical trials for a potential therapy can cost hundreds of millions of dollars. The human costs are even greater (pg 423, col. 1). For example, while 12 clinical trials were tested for the treatment of ALS, all but one failed in the clinic (pg 423, col. 2). Experiments necessary in preclinical animal models to characterize new drugs or therapeutic compounds are expensive, time-consuming, and will not, in themselves, lead to new treatments. But without this upfront investment, financial resources for clinical trials are being wasted and [human] lives are being lost (pg 424, col. 1). Animal models are highly variable, and require a large number of animals per test group. Before assessing a drug’s efficacy, researchers should investigate what dose animals can tolerate, whether the drug reaches the relevant tissue at the required dose and how quickly the drug is metabolized or degraded by the body. We estimate that it takes about $30,000 and 6–9 months to characterize the toxicity of a molecule and assess whether enough reaches the relevant tissue and has a sufficient half-life at the target to be potentially effective. If those results are promising, then experiments to test whether a drug can extend an animal’s survival are warranted — this will cost about $100,000 per dose and take around 12 months. At least three doses of the molecule should be tested; this will help to establish that any drug responses are real and suggest what a reasonable dosing level might be. Thus, even assuming the model has been adequately characterized, an investment of $330,000 is necessary just to determine whether a single drug has reasonable potential to treat disease in humans. It could take thousands of patients, several years and hundreds of millions of dollars to move a drug through the clinical development process. The investment required in time and funds is far beyond what any one lab should be expected to do. (pg 425, col.s 2-3). The human costs are even greater: patients with progressive terminal illnesses may have just one shot at an unproven but promising treatment. Clinical trials typically require patients to commit to year or more of treatment, during which they are precluded from pursuing other experimental options (pg 423, col.2 1-3).
Greenberg (Gene Therapy for heart failure, Trends in Cardiovascular Medicine 27: 216-222, 2017) is considered relevant prior art for taught that despite success in experimental animal models, translating gene transfer strategies from the laboratory to the clinic remains at an early stage (Abstract). The success of gene therapy depends on a variety of factors that will ultimately determine the level of transgene expression within the targeted cells. These factors include the vector used for delivery, the method and conditions of delivery of the vector to the [target tissue], the dose that is given and interactions between the host and the vector that alter the efficiency of transfection of [target] cells (e.g. pg 217, col. 1). Failure of therapeutic results may arise because the vector DNA levels were at the lower end of the threshold for dose-response curves in pharmacology studies, and/or only a small proportion of target cells were expressing the therapeutic transgene (e.g. pg 220, col. 1). Although the use of AAVs for gene therapy is appealing, additional information about the best strain of AAVs to use in human patients is needed. Experience indicates that there is a need to carefully consider the dose of the gene therapy vector; however, this has proved to be difficult in early phase developmental studies due to the complexity and cost of such studies (e.g. pg 221, col. 1).
Maguire et al (Viral vectors for gene delivery to the inner ear, Hearing Research 394: e107927, 13 pages, doi.org/10.1016/j.heares.2020.107927, 2020) is considered relevant post-filing art for taught that despite the progress with AAV vectors in the inner ear, little is known regarding the mechanism of transduction of specific cells by AAV within the cochlea (e.g. pg 2, col. 2). There are limitations to what experiments in mice can tell us about the true translation potential of a new therapeutic (e.g. pg 8, col. 2), e.g. species-related physiological differences between mice and humans (e.g. pg 9, col. 1). The AAV dosage is a significant factor in achieving transduction of the target cell, as insufficient dosage may achieve no transduction of the target cells (e.g. pg 9, col. 2).
Tobias (Mouse Study Used in Research, Multiple Sclerosis News Today, multiplesclerosisnewstoday.com/news-posts/2023/09/08/lets-not-get-overexcited-about-any-mice-study-used-research/; September 8, 2023) is considered relevant art for having taught that, “Mice exaggerate and monkeys lie, some researchers jokingly say. (Or is it the other way around?)” The odds of an experimental treatment making it from mouse or monkey to human are very low. Less than 8% of cancer treatments make it from animal studies into a clinical setting, where they’re tested on people, and only 10% of the medications in those clinical trials make it through to government approval. No wonder some researchers joke about mice and monkeys lying and exaggerating.
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.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claims.
Claim Rejections - 35 USC § 102
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 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.
6. Claim(s) 1 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by van Beek et al (GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma, Int. J. Cancer 145(4): 1111-1124, doi.org/10.1002/ijc.32181; available online February 4, 2019), as evidenced by GeneCard (www.genecards.org/cgi-bin/carddisp.pl?gene=TNFRSF18; last visited January 12, 2026).
With respect to Claims 1 and 7, van Beek et al is considered relevant prior art for having taught a composition comprising CD8+ TCR T cells expressing a TCR that recognizes a tumor antigen (e.g. Abstract, “proliferative responses of…CD8+ tumor infiltrating lymphocytes to tumor antigens”; pg 1122, col. 2), wherein said TCR T cells express CD8+ and TNFRSF18 (syn. GITR) (e.g. pg 1114, col. 2, “GITR ligation enhances CD8+ TIL proliferation”).
Thus, van Beek et al anticipate the claims.
7. Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Duhen et al (Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors, Nature Communications 9: e2724, 13 pages, doi.org/10.1038/s41467-018-05072-0; available online July 13, 2018; of record in IDS).
With respect to Claim 1, Duhen et al is considered relevant prior art for having taught a composition comprising CD8+ TCR T cells expressing a TCR that recognizes a tumor antigen, wherein said TCR T cells express CD8+ and CXCL13 (e.g. Supplementary Table 1).
Thus, Duhen et al anticipate the claim(s).
8. Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Workel et al (A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer, Cancer Immunol. Res. 7(5): 784-796, doi.org/10.1158/2326-6066.CIR-18-0517; available online May 1, 2019).
With respect to Claim 1, Workel et al is considered relevant prior art for having taught a composition comprising CD8+ TCR T cells expressing a TCR that recognizes a tumor antigen (e.g. pg 785, col. 1, “TILs.. are induced by (neo)antigen-specific adaptive immunity”), wherein said TCR T cells express CD8+ and CXCL13 (e.g. Abstract).
Thus, Workel et al anticipate the claim(s).
Workel et al taught that CXCL13+, CD8+ T cells correlates to improved survival, irrespective of neoantigen burden (e.g. pg 792, col. 2).
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 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.
9. Claims 7 and 12 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Beek et al (GITR ligation enhances functionality of tumor-infiltrating T cells in hepatocellular carcinoma, Int. J. Cancer 145(4): 1111-1124, doi.org/10.1002/ijc.32181; available online February 4, 2019; of record), as applied to Claims 1 and 7 above, in view of Fernandez-Poma et al (Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy, Cancer Research 77(13): 3672-3684, 2017).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claims 1 and 7, van Beek et al is considered relevant prior art for having taught a composition comprising CD8+ TCR T cells expressing a TCR that recognizes a tumor antigen (e.g. Abstract, “proliferative responses of…CD8+ tumor infiltrating lymphocytes to tumor antigens”; pg 1122, col. 2), wherein said TCR T cells express CD8+ and TNFRSF18 (syn. GITR) (e.g. pg 1114, col. 2, GITR ligation enhances CD8+ TIL proliferation”).
van Beek et al taught that GITR ligation enhances CD8+ TIL proliferation (e.g. pg 1114, col. 2) and is able to enhance the responsiveness of tumor-infiltrating lymphocytes from HCC patients (e.g. pg 1118, col. 2), including effector cytokine and granzyme B production (e.g. pg 1120, col. 1-2, joining para), and thus may be a promising immunotherapeutic for patients with HCC (e.g. pg 1122, col. 2).
van Beek et al do not teach:
i) formulating CD8+ TCR T cells in a pharmaceutical composition; nor
ii) administering the CD8+ TCR T cells to a subject suffering from cancer.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 7 and 12, 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 CD8+ tumor-infiltrating lymphocytes (e.g. pg 3674, col. 1, Methods, ACT experiments). Fernandez-Poma et al taught the CD8+ TILs naturally recognize tumor antigens (e.g. Abstract, “antigen specificities”; Introduction, “TILs are naturally occurring T cells able to recognize tumor-associated antigens (Ag), including neo-Ags”).
Fernandez-Poma et al taught that enrichment and expansion of CD8+ TILs improves the efficacy of TIL therapy, including delayed tumor growth and enhanced survival (e.g. pg 3680, col. 1).
Resolving the level of ordinary skill in the pertinent art.
People of the ordinary skill in the art will be highly educated individuals such as medical doctors, scientists, or engineers possessing advanced degrees, including M.D.'s and Ph.D.'s. Thus, these people most likely will be knowledgeable and well-read in the relevant literature and have the practical experience in immunology, cancer biology and cellular immunotherapy. Therefore, the level of ordinary skill in this art is high.
"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1397 (2007). "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at ___, 82 USPQ2d at 1396.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
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 HCC patients comprising the step of administering to said patients a pharmaceutical composition comprising CD8+, GITR+ tumor-infiltrating lymphocytes that recognize the patient’s tumor-specific antigens with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) administering a pharmaceutical composition comprising CD8+ TCR T tumor-infiltrating lymphocytes to mouse tumor xenograft subjects is feasible, and that enrichment and expansion of CD8+ TILs improves the efficacy of TIL therapy, including delayed tumor growth and enhanced survival (Fernandez-Poma et al); and
ii) GITR ligation enhances CD8+ TIL proliferation, is able to enhance the responsiveness of tumor-infiltrating lymphocytes from HCC patients, including effector cytokine and granzyme B production, and thus may be a promising immunotherapeutic for patients with HCC (van Beek et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
10. Claims 7 and 12 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Workel et al (A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer, Cancer Immunol. Res. 7(5): 784-796, doi.org/10.1158/2326-6066.CIR-18-0517; available online May 1, 2019), as applied to Claim(s) 1 above, in view of Fernandez-Poma et al (Expansion of Tumor-Infiltrating CD8+ T cells Expressing PD-1 Improves the Efficacy of Adoptive T-cell Therapy, Cancer Research 77(13): 3672-3684, 2017; of record).
Determining the scope and contents of the prior art, and Ascertaining the differences between the prior art and the claims at issue.
With respect to Claim 1, Workel et al is considered relevant prior art for having taught a composition comprising CD8+ TCR T cells expressing a TCR that recognizes a tumor antigen (e.g. pg 785, col. 1, “TILs.. are induced by (neo)antigen-specific adaptive immunity”), wherein said TCR T cells express CD8+ and CXCL13 (e.g. Abstract).
Workel et al taught that CXCL13+, CD8+ T cells correlates to improved survival, irrespective of neoantigen burden (e.g. pg 792, col. 2).
Workel et al do not teach:
i) formulating CD8+ TCR T cells in a pharmaceutical composition; nor
ii) administering the CD8+ TCR T cells to a subject suffering from cancer.
However, prior to the effective filing date of the instantly claimed invention, and with respect to Claim(s) 7 and 12, 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 CD8+ tumor-infiltrating lymphocytes (e.g. pg 3674, col. 1, Methods, ACT experiments). Fernandez-Poma et al taught the CD8+ TILs naturally recognize tumor antigens (e.g. Abstract, “antigen specificities”; Introduction, “TILs are naturally occurring T cells able to recognize tumor-associated antigens (Ag), including neo-Ags”).
Fernandez-Poma et al taught that enrichment and expansion of CD8+ TILs improves the efficacy of TIL therapy, including delayed tumor growth and enhanced survival (e.g. pg 3680, col. 1).
Considering objective evidence present in the application indicating obviousness or nonobviousness.
The focus when making a determination of obviousness should be on what a person of ordinary skill in the pertinent art would have known at the time of the invention, and on what such a person would have reasonably expected to have been able to do in view of that knowledge. This is so regardless of whether the source of that knowledge and ability was documentary prior art, general knowledge in the art, or common sense. M.P.E.P. §2141.
The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings); and Ex parte Levengood, 28 USPQ2d 1300 (Bd. Pat. App. & Inter. 1993) (reliance on logic and sound scientific reasoning). See MPEP §2144.
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 cancer patients comprising the step of administering to said patients a pharmaceutical composition comprising CD8+, CXCL13+ tumor-infiltrating lymphocytes that recognize the patient’s tumor-specific antigens with a reasonable expectation of success because those of ordinary skill in the art previously recognized the scientific and technical concepts that:
i) administering a pharmaceutical composition comprising CD8+ TCR T tumor-infiltrating lymphocytes to mouse tumor xenograft subjects is feasible, and that enrichment and expansion of CD8+ TILs improves the efficacy of TIL therapy, including delayed tumor growth and enhanced survival (Fernandez-Poma et al); and
ii) CXLC13+, CD8+ T cells correlates to improved survival, irrespective of neoantigen burden, as the CXLC13+, CD8+ T cells promote formation of tertiary lymphoid structures associated with greater immune control of cancer growth and improved prognosis (Workel et al).
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
11. No claims are allowed.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638