DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's election filed April 14, 2026 without traverse of Group I, (claims 1-15 and 18-20) is acknowledged.
Applicant’s further election filed April 14, 2026 with traverse of Species 1 (alternative biomarker species): (a) claim 3; and Species 2 (alternative method steps performed in addition to claim 9 method steps): (a) claims 11 and 12 is acknowledged. The traversal is on the ground(s) that: (i) the identified biomarker sets recite a plurality of alternative usable members and the required search poses no serious burden; and (ii) claim 13, like claim 12, depends from claim 11, which depends from claim 9, therefore search for claims 11 and 12 would be required for search of claim 13 and so the claims should be considered together; and similar arguments as to claims 14-15; Applicant urges that it is reasonable for the Office to search the additional method steps because there is no serious burden. This is not found persuasive for the following reasons:
The instant application is national stage application filed under the provisions of 35 U.S.C § 371, and not a direct US filing or bypass continuation filed under the provisions of 35 U.S.C § 111(a). Therefore, as provided in 37 CFR 1.475(a), the application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept. As set out in the restriction requirement of January 22, 2026, the indicated species lack unity of invention because they are not so linked as to form a single general inventive concept under PCT Rule 13.1 (The international application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept (“requirement of unity of invention”)) because the common technical feature linking the groups of species is a reactive T-cell; a reactive T-cell is not a special technical feature in view of Fuchs et al. (cited in IDS), which teaches that T-cells play an important role in adaptive immunity and demonstrate a method for their identification. See MPEP § 1850 for more regarding PCT rule 13 and unity of invention. In other words, the common technical feature of: a reactive T-cell does not make a contribution over the art in view of Fuchs et al., and therefore unity of invention is lacking between the indicated groups of inventions and species.
To address Applicant’s arguments regarding search burden, search burden is not a formal consideration under PCT Rule 13.1 for deciding unity.
The requirement is therefore still deemed proper and is therefore made FINAL.
Accordingly, claims 1-20 are pending; and claims 1-3, 7-12, and 18-20 are presently under consideration. Claims 4-6 and 13-17 are withdrawn from further consideration as being drawn to a non-elected invention/species.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification Objections
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “FACS,” pg. 11, ln. 17), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Applicant should review the specification for other trademarks and make corrections as required.
b. There are references in this specification that should be placed on an information disclosure statement if application would like them considered.
c. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
d. There are also what appears to be claims under an additional embodiment section; if they are claims they should be placed on a separate page.
Objections to the Claims
5. Claims 9, 11-12, and 19 are objected to because of the following informality:
These claims recite the abbreviation “TCR,” which stands for T-cell receptor, without defining the abbreviation at its first instance in the claims. These claims are therefore incomplete.
Double Patenting
6. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/proces/file/efs/guidance/eTD-info-I.jsp.
Instant claims 1, 2, 7, 9-12, and 18-19 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 2, 7, 9-12, and 18-19 of copending Application No. 18/552,096 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons:
Claims 1, 2, 7, 9-12, and 18-19 of copending Application No. 18/552,096 are identical to claims 1, 2, 7, 9-12, and 18-19 of instant application, except claim 1 copending Application No. 18/552,096 additionally recites: “preferably wherein said T-cell activating antigen is a cancer antigen or an autoimmune T- cell activating antigen.” This “preferably wherein” clause does not confer patentable distinctness between the claims because it is optional language. The claims therefore encompass the indicated claims of instant application.
Therefore, the conflicting claims are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection since the claims directed to the patentably indistinct invention have not in fact been patented.
Claim Rejections - 35 USC § 112
7. 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.
Claims 9-10 and 19 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
a. Claim 10 depends from claim 1 and recites: “wherein expression of at least one biomarker of step a).” The term “biomarker” lacks antecedent basis in claim 1, thereby rendering the claim unclear. Appropriate clarification and/or correction is requested.
b. Claim 20 depends from claim 9 and recites: “expression of the nucleic acid sequences encoding the amino acid sequences of step (B).” The term “nucleic acid sequence” lacks antecedent basis in claim 9, thereby rendering the claim unclear. Appropriate clarification and/or correction is requested.
c. Claim 9 recites the feature: “(B) providing the amino acid sequences of at least the complementarity determining regions (CDRs) of the TCR of the reactive T-cell identified in step (A).” Although the instant specification provides a definition for “providing a sequence” at para. [0056] to include: “any and all means and methods of providing information on said sequence,” it remains unclear if the claim-recited feature “providing the amino acid sequence” includes features beyond expressing the amino acid sequences in the T-cells. For example, does providing the amino acid sequence include adding the amino acid sequence to culture media? Appropriate clarification and/or correction is requested.
d. Claim 9 recites the feature: “(C) identifying a TCR binding to an activating antigen presented on a cell.” Although the instant specification provides a definition for the related concept of “identifying a T-cell reactive to cells presenting a T-cell activating antigen” at para. [0032] to include: the “broad sense including any and all means and methods of providing information on a reactive T-cell allowing determination of at least the CDR sequences of its TCR,” it remains unclear if the claim-recited feature of identifying TCR binding requires confirming that the TCR has bound to an activating antigen present on a cell, or if the feature requires any active steps that could not be practiced by the mind alone. Does “identifying a TCR binding to an activating antigen present on a cell” require anything more than “providing information on a reactive T-cell allowing determination of at least the CDR sequences of its TCR,” or choosing a TCR that binds to an activating antigen? Appropriate clarification and/or correction is requested.
e. Claim 12 depends from claim 11 (and thus 9) and recites the feature: “B2) determining binding of the TCR expressed in step B1.” Although the instant specification provides a definition of “determining binding” at para. [0023] to include: “Binding of a T-cell receptor to an antigen can be determined by methods known to the skilled person, e.g. by methods as specified herein in the Examples, or e.g. in a tetramer assay. Preferably, binding of the TCR to an epitope presented on an MHC activates the T-cell. Activation biomarkers of various types of T-cells are known in the art and include in particular CD69, CD137, CD27, TRAP/CD40L, and CD134,” it remains unclear if the “determining binding” feature requires any additional steps other than determining the presence of instantly claimed biomarkers, or if the feature requires any active steps that could not be practiced by the mind alone. Does “determining binding” require anything more determining the presence of claim-recited biomarkers, or choosing TCRs based on the biomarkers? Appropriate clarification and/or correction is requested.
Claim Rejections - 35 USC § 101
8. 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.
9. Claims 1-3, 7-12, and 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claims 1-3, 7-12, and 18-20 are directed to a judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because of the reasons set forth below.
The claims are drawn to a method of identifying a T-cell reactive to cells of a subject presenting a T-cell activating antigen (reactive T-cell), comprising (a) determining expression of at least one of CXCL13, CCL3, CCL3L1, CCL4, and CCL4L2 in T-cells from a sample of said subject; and (b) identifying a reactive T-cell based on the determination of step (a).
The claim recites or requires a series of steps/acts, i.e., (a) determining expression of at least one of CXCL13, CCL3, CCL3L1, CCL4, and CCL4L2 in T-cells from a sample of said subject; and (b) identifying a reactive T-cell based on the determination of step (a) in order to; identify a T-cell reactive to cells of a subject presenting a T-cell activating antigen (reactive T-cell). Thus, the claim is directed to a process, which is one of the statutory categories of invention. The claims describe a correlation or relationship between T-cell biomarkers and T-cells that are reactive to cells presenting T-cell activating antigen; the claims therefore are directed to a judicial exception because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo. Additionally, the correlation/relationship between the recited biomarkers and reactive T-cells is known in the art; see e.g., Boroughs et al. (WO 2020092455 A2; published May 7, 2020) at claim 35. Additionally, steps of “determining” and “identifying” are abstract ideas, and thus the claims are directed towards a judicial exception. The steps of determining and identifying are recited at a high level of generality that imposes no limits on how the steps are accomplished. When interpreting the claim during examination, it is apparent that the steps of determining and identifying could be performed by a human using mental steps or basic critical thinking. Similar mental processes have been held by the courts to be abstract ideas, e.g., collecting and comparing known information in Classen, or comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC. The specific information that is being determined (e.g., T-cell biomarkers) merely narrows the abstract idea, which does not make the identifying step less abstract and is not sufficient to provide eligibility on its own. Thus, the claim is directed to an abstract idea.
The claims recite elements/steps in addition to the judicial exception(s) that are recited at a high level of generality, must be used/taken by others to apply the judicial exception(s), are well-understood, purely conventional or routine, are insignificant extra-solution activity, (e.g., are merely appended to the judicial exception(s) and amount to nothing more than a mere field of use). For instance, claim 9 recites a method of “identifying TCR binding to a T-cell antigen presented on a cell,” and requires detecting binding of the identified TCR to an activated antigen presented on a cell. The claim is directed to subject matter: validating that the identified TCR indeed binds to TCR activating antigen. However, such validation steps are routine; there are no non-conventional steps recited in the claims to impose a meaningful limit on the method.
The “determining” and “identifying” steps simply tell the relevant audience about the relevant natural laws, at most adding a suggestion that the person identifying reactive T-cells should take those laws into account when identifying the reactive T-cells. The steps also tell the relevant audience to determine expression of the biomarkers through whatever process the relevant audience wishes to use. The claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately. Taken together, the claims do not amount to significantly more than the natural law itself.
Consideration of the additional elements as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. Unlike the eligible claim in which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim here does not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exception into a patent eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself.
Claim Rejections - 35 USC § 102
11. 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.
Claims 1-3, 7-12, and 18-20 are rejected under 35 U.S.C 102(a)(2) as being anticipated by Boroughs et al. (WO 2020092455 A2; published May 7, 2020).
Claim 1 is drawn to a method of identifying a T-cell reactive to cells of a subject presenting a T-cell activating antigen (reactive T-cell), comprising (a) determining expression of at least one of CXCL13, CCL3, CCL3L1, CCL4, and CCL4L2 in T-cells from a sample of said subject; and (b) identifying a reactive T-cell based on the determination of step (a).
Claim 2 is drawn to the method of claim 1, wherein step (a) comprises determining expression of at least two of CXCL13, CCL3, CCL3L1, CCL4, and CCL4L2.
Claim 3 is drawn to the method of claim 1, wherein step (a) comprises further determining expression of at least one biomarker selected from the list consisting of TNFRSF9, VCAM1, TIGIT, HAVCR2, GZMB, GPR183, CCR7, IL7R, VIM, LTB, and JUNB.
Claim 7 is drawn to the method of claim 1, wherein said T-cell activating antigen is a cancer antigen, and wherein said sample is a tumor sample.
Claim 8 is drawn to the method of claim 7, wherein said cancer is pancreatic cancer, colorectal cancer, or any other primary or metastatic solid tumor type.
Claim 9 is drawn to a method of identifying a TCR binding to a T-cell activating antigen presented on a cell of a subject, said method comprising (A) identifying a reactive T-cell according to the method of claim 1, (B) providing the amino acid sequences of at least the complementarity determining regions (CDRs) of the TCR of the reactive T-cell identified in step (A); and, hereby, (C) identifying a TCR binding to an activating antigen presented on a cell.
Claim 10 is drawn to the method of claim 1, wherein expression of at least one biomarker of step a) is determined by single-cell sequencing.
Claim 11 is drawn to the method of claim 9, wherein said method comprises further step B1) expressing a TCR comprising at least the CDRs determined in step B) in a host cell.
Claim 12 is drawn to the method of claim 11, wherein said method further comprises further step B2) determining binding of the TCR expressed in step B1) to a T-cell activating antigen.
Claim 18 is drawn to the method of claim 1, wherein said T-cell(s) is/are CD8+ T-cell(s) or CD4+ T-cells.
Claim 19 is drawn to the method of claim 9, wherein said TCR comprises a TCR alpha chain and a TCR beta chain.
Claim 20 is drawn to the method of claim 9, wherein expression of the nucleic acid sequences encoding the amino acid sequences of step (B) is determined by single-cell sequencing.
Claim interpretation: claims 9 and 12 respectively recite features: “identifying a TCR binding to an activating antigen presented on a cell” and “determining binding of the TCR.” As discussed above in the 35 U.S.C 112(b) rejections, the breadth of these terms is unclear in view of the specification. Accordingly, the terms “identifying” and “determining” are afforded their broadest reasonable interpretation: the terms identifying and determining include “choosing,” e.g., choosing a TCR to bind to an activating antigen presented on a cell.
Boroughs et al. is directed to gene expression profiles and signatures of CAR T cells (see the abstract). Claim 1 of Boroughs et al. recites: a method of identifying a candidate CAR T cell comprising: measuring expression of a gene signature of a CAR T cell and identifying the CAR T cell as the candidate CAR T cell if the CAR T cell a gene signature selected from: […] q) a T cell activation gene signature.
Boroughs et al. discloses the T cell activation gene signature comprises one or more genes selected from the group consisting of: IFNG, CCL4, CCL3, IL3, XCL1, CSF2, GZMB, FABP5, XCL2, LTA, LAG3, MIR155HG, TNFRSF4, TNFRSF9, PIM3, IL13, ZBED2, PGAM1, EIF5A, IL5 and an any combination thereof at para. [0025] and claim 35.
Boroughs et al. further discloses that “the T cell activation gene signature can be a TCR activation gene signature” at para. [0115], thereby necessarily also disclosing the instantly claimed reactivity to T-cell activating antigen feature; and that the CAR T cell or population thereof may be obtained from or derived from a subject to be treated at para. [0044].
Accordingly, Boroughs et al. teaches identifying a T-cell reactive to cells of a subject presenting a T-cell activating antigen (reactive T-cell), comprising (a) determining expression of instantly claimed biomarkers in T-cells from a sample of said subject; and (b) identifying a reactive T-cell based on the determination of step (a). (Claims 1-3)
Boroughs et al. further discloses that “the T cell expresses an endogenous T cell receptor (TCR) or chimeric antigen receptor (CAR) specific for a tumor antigen” at para. [0066]; and that “examples of solid tumors, such as sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer” at para. [0275]. (Claims 7-8)
Boroughs et al. further discloses expressing identified TCR (necessarily including at least CDR) in a host cell; and identifying binding of TCR to activating antigen presented on a cell:
First, Boroughs et al. discloses at para. [0449]: In another aspect, the present invention provides for a method of preparing a CAR T cell specific for a tumor antigen comprising identifying TCRs according to any embodiment herein and generating a CAR T cell comprising the antigen-binding portion of the TCR identified.
Next, Boroughs et al. discloses at para. [0165]-[0166]; [0171]: In one embodiment, the CAR of the invention comprises an antigen binding domain that binds to an antigen on a target cell. Examples of cell surface markers that may act as an antigen that binds to the antigen binding domain of the CAR include those associated with viral, bacterial and parasitic infections, autoimmune disease, and cancer cells. The choice of antigen binding domain depends upon the type and number of antigens that are present on the surface of a target cell. For example, the antigen binding domain may be chosen to recognize an antigen that acts as a cell surface marker on a target cell associated with a particular disease state; A CAR described herein can comprise an antigen binding domain (e.g., antibody or antibody fragment, TCR or TCR fragment) that binds to a tumor-supporting antigen (e.g., a tumor-supporting antigen as described herein). As also discussed above, Boroughs et al. is concerned with T-cell activation signatures, and therefore necessarily also with the antigens the cause T-cell activation. (Claims 9 and 11-12).
Boroughs et al. further discloses use of single-cell sequencing to determine biomarkers and TCRs; e.g. at para. [0125] “Various aspects and embodiments of the invention may involve analyzing gene signatures, protein signatures, and/or other genetic signatures based on single cell analyses (e.g. single cell RNA sequencing).” (Claims 10, 20)
Boroughs et al. further discloses T-cell are CD8+ T-cells or CD4+ T-cells at para. [0011]. (Claim 18)
Last, Boroughs et al. necessarily discloses a TCR comprising alpha chain and beta chain; e.g. at para. [0894] “Various strategies may for example be employed to genetically modify T cells by altering the specificity of the T cell receptor (TCR) for example by introducing new TCR a and b chains with selected peptide specificity.” (Claim 19)
Accordingly, Boroughs et al. anticipates claims 1-3, 7-12, and 18-20.
Conclusion
12. No claim is allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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