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 .
Election/Restrictions
Applicant’s election without traverse of Group IV, claim 51, in the reply filed on 12/19/2025 is acknowledged.
Claims 32-50 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/19/2025. Claims 1-31 are cancelled.
Specification/Claim Objections
The Specification and claims are objected to. It is noted that the Specification and claim 32 (nonelected but parent claim to elected claim 51) refers to SEQ ID NO:2 as the light chain and SEQ IDNO:1 as the heavy chain. SEQ ID NO:2 is the larger polypeptide and Neumaier (CANCER RESEARCH 50. 2128-2134. April 1, 1990) published the sequence of the T84.66 monoclonal antibody and supports that SEQ ID NO:1 of the invention is the light chain and SEQ ID NO:2 is the sequence of the heavy chain (See Neumaier, Figure 1). It was determined that the ScFv of the invention is that of monoclonal T84.66 as Example 1 refers to SEQ ID NO:18 which encodes the T84.66 ScFv as determined by a search of the NCBI protein database.
Claim Rejections - 35 USC § 102/103
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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
1) Claim(s) 51 is rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Cha (The Journal of Immunology, Vol. 204, Issue 1 Supplement, 5/1/2020, p. 239.25, https://doi.org/10.4049/jimmunol.204.Supp.239.25) as evidenced by or in view of Oldham (2017, Expert Opinion on Biological Therapy, 17:8, 961-978, DOI: 10.1080/14712598.2017.1339687) and Zhang (Molecular Therapy Vol. 25 No 5 May 2017, 1248-1258).
Claim 51 is drawn to a method for preventing or treating cancer, the method comprising a step of administering a host cell expressing a chimeric antigen receptor (CAR) comprising a carcinoembryonic antigen (CEA) binding domain, a hinge region, a transmembrane domain (TM), a costimulatory domain and a signaling domain wherein the CEA binding domain comprises the amino acid sequences set forth by SEQ ID NO:1 and SEQ ID NO:2.
SEQ ID NO:1 encodes the light chain from the anti-CEA monoclonal T84.66.
PNG
media_image1.png
277
678
media_image1.png
Greyscale
SEQ ID NO:2 encodes the heavy chain from the anti-CEA monoclonal T84.66.
PNG
media_image2.png
335
673
media_image2.png
Greyscale
Cha taught administering T-cells expressing an anti-CEA CAR construct derived from murine anti-CEA antibody T84.66. Thus, the antibody comprised the VH and VL domains set forth by the sequences in SEQ ID NO:1 and SEQ ID NO:2. Cha does not discuss the other domains present in the CAR but these domains were well known to be included in CARs.
CARs, by definition, comprise an antigen binding domain, a hinge region, a transmembrane domain (TM), a costimulatory domain and a signaling domain, as evidenced by Oldham. Oldham depicts a generic CAR with a variety of options for the various domains in Figure 1, including an ScFv, hinge, TM, costimulatory and signaling domains.
PNG
media_image3.png
212
434
media_image3.png
Greyscale
For example, Zhang teaches CAR T-cell therapy with T-cells expressing a CAR comprising a CEA scFV derived from a different monoclonal antibody, BW431/26, which is mentioned in the abstract of Cha. Like all third generation CARs, the CAR of Zhang comprises an IgG4 hinge, CD28 TM, CD28 costimulatory domain and a CD3z signaling domain (see page 1255, left column). The only difference in the CAR of Zhang, compared to that claimed, is that the binding domains are derived from different anti-CEA monoclonals.
If it cannot be presumed that the CAR in the CAR-T cell therapy of Cha comprised a hinge, TM, costimulatory and signaling domain, it would have been obvious at the time of filing to include a hinge, TM, costimulatory and signaling domain in the anti-CEA CAR-T cell therapy of Cha to arrive at the invention as claimed. One would have been motivated to include those domains because not only did Oldham teach that they were components of all CARs, Zhang had used the same treatment with a CAR comprising a different anti-CEA domain and that CAR also comprised a hinge, TM, costimulatory and signaling domain. Likewise, one would have been motivated to exchange the CEA binding domain of Zhang with that of Cha to alter the affinity of the CAR T-cell to determine if different binding affinities treated different cancers with better efficiencies. One would have had a reasonable expectation of success in making the combination as Oldham taught the missing structure in the teachings of Cha was standard and routine in the art.
2) Claim 51 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Molecular Therapy Vol. 25 No 5 May 2017, 1248-1258). in view of Yazaki (Protein Engineering, Design & Selection vol. 17 no. 5 pp. 481–489, 2004), US 7,273,608 (‘608 to Yaxaki; IDS), Szekanecz (2011, 2nd International Cancer Immunotherapy and Immunomonitoring Conference, Budapest, Hungary, Abstract book, Redefining Cancer Therapy) and Polli (Journal of Pharmaceutical Sciences, Volume 108, Issue 1, January 2019, Pages 674-691) in further view of Neumaier (CANCER RESEARCH 50. 2128-2134. April 1, 1990|).
Claim 51 is drawn to a method for preventing or treating cancer, the method comprising a step of administering a host cell expressing a chimeric antigen receptor (CAR) comprising a carcinoembryonic antigen (CEA) binding domain, a hinge region, a transmembrane domain (TM), a costimulatory domain and a signaling domain wherein the CEA binding domain comprises the amino acid sequences set forth by SEQ ID NO:1 and SEQ ID NO:2. Note that there is no limitation in the claim regarding a treatment effect or efficacy.
Zhang teaches CAR T-cell therapy with T-cells expressing a CAR comprising a CEA scFV derived from antibody BW431/26. The CAR of Zhang comprises an IgG4 hinge, CD28 TM, CD28 costimulatory domain and a CD3z signaling domain (see page 1255, left column). The only difference in the CAR of Zhang, compared to that claimed, is that the binding domains are derived from different anti-CEA monoclonals. However, several different anti-CEA monoclonals were known at the time of filing.
For example, Yazaki teaches that T84.66 exhibits high specificity and affinity for tumor associated CEA. ‘608 teaches the T84.66 monoclonal has had extensive clinical history and use in treatment of over 200 patients (column 2). Szekanecz teaches a number of antibodies to CEA have undergone clinical trials including BW431/26 and T84.66 (last para). Polli teaches T84.66 is a “standard” anti-CEA mAb that demonstrates strong binding.
Neumaier taught the availability and sequence information for the T84.66 anti-CEA monoclonal (SEQ ID NO:1 and SEQ ID NO:2).
It would have been obvious at the time of filing to substitute the BW431/26 anti-CEA scFv used in the treatment method of Zhang with the T84.66 anti-CEA scFv taught by each of Yazaki, Szekanecz and Polli to arrive at the invention as claimed. One would have been motivated to make such a substitution as both Yazaki and Polli discuss the strong binding properties of the T84.66 mAB and Szekanecz taught the both BW431/26 and T84.66 had been used in clinical trials to treat cancers associated with elevated CEA. One would have had a reasonable expectation of success in making the combination as Neumaier provided the sequences needed to carry out the substitution, which was standard and routine in the art.
The combination of prior art cited above in all rejections under 35 U.S.C. 103 satisfies the factual inquiries as set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Once this has been accomplished the holdings in KSR can be applied (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. ___, 82 USPQ2d 1385 (2007)): "Exemplary rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
In the present situation, rationales A,B and E are applicable. The claims merely require the combination/substitution of known anti-CEA scFvs in a CAR T-cell to treat cancers that express CEA. The combination of the prior art references would lead to a predictable result absent results to the contrary. Thus, the teachings of the cited prior art in the obviousness rejection above provide the requisite teachings and motivations with a clear, reasonable expectation. The cited prior art meets the criteria set forth in both Graham and KSR.
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.
3) Claim 51 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer associated with increased carcinoembryonic antigen (CEA) expression comprising systemically administering T-cells expressing a chimeric antigen receptor comprising a CEA binding domain, a hinge region, a transmembrane domain a costimulatory domain and a signaling domain wherein the treatment effect is a stabilized cancerous disease state, does not reasonably provide enablement for treatment of any cancer type (other than that exhibiting CEA expression) using any cell type (other than T-cell) by any route of administration (other than systemic) wherein the treatment effect is curative or wherein the cancerous state is prevented. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
MPEP §2164.01(a), 4th paragraph, provides that, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1157, 1562; 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
The nature of the invention relates to treatment of cancer using a T-cell expressing a chimeric antigen receptor (CAR) that targets carcinoembryonic antigen (CEA), a protein expressed on some types of cancer that is rarely expressed on normal adult cells.
Claim 51 is broadly drawn to the treatment of any type of cancer using any cell type where the cells are administered by any mode of administration.
The guidance in the specification relates to generating a CAR T-cell expressing a CAR where the antigen binding domain is derived from a monoclonal antibody, T84.66 (determined based on the reference to SEQ ID NO:18 in Example 1), that binds CEA. The working examples with this CAR are all in vitro experiments with no in vivo studies to support the claimed method of treating cancer. However, at the time of filing, a different CEA antigen binding domain had been used in clinical trials of CAR T-cell therapy (see Zhang, Molecular Therapy Vol. 25 No 5 May 2017, 1248-1258).
Zhang taught the use of adoptive T cell therapy as a promising anti-tumor treatment. Genetically modified T cells that express chimeric antigen receptors (CARs) eliminate tumor cells by binding to tumor antigens through antigen-antibody recognition. This role is carried out by the function of T-cells and cannot be carried out by any cell type as broadly claimed (i.e. fibroblast, cardiomyocyte, adipocyte etc). Raskov teaches cytotoxic T cells as the most powerful effectors in the anticancer immune response (British Journal of Cancer, (2021) 124:359–367; https://doi.org/10.1038/s41416-020-01048-4). Additionally, the Specification teaches expressing the anti-CEA CAR only in T-cells (see Example 3).
With regard to cancer cell type to be treated by the claimed method, Zhang and the specification only teach toxicity of anti-CEA CAR T-cells on cancers that express CEA. The examples in the specification are in vitro while Zhang, used the CEA binding domain derived from the BW431/25 monoclonal, taught both in vivo and in vitro recognition of cancer types expressing CEA, including breast cancer and colorectal cancer. The anti-CEA CAR is not designed to recognize cancer types that do not overexpress CEA.
The claims are broad with regard to the mode of administration. Claims encompass any mode including topical, oral, intramuscular and intratracheal, for example. The specification fails to provide any in vivo examples and Zhang taught a clinical trial using patients that were unresponsive to other treatments and had advanced, metastatic disease. Zhang taught a stabilizing response when cells were administered systemically. Neither Zhang nor the specification taught remission, cure, or prevention and neither taught treatment of less advanced stages prior to metastasis. There is nothing on the record to support treatment or cure beyond stabilizing the disease state via systemic administration.
Thus, given the breadth of the claims with regard to treatment and prevention of any cancer with any cell type, the state of the art supporting treatment of cancers overexpressing CEA using systemic delivery of T-cells and a CEA specific CAR and the lack of guidance with regard to use of other cells types, other modes of delivery and treatment of cancers that do not express CEA, it would have required undue experimentation at the time of filing to carry out the invention as broadly claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALARIE BERTOGLIO whose telephone number is (571)272-0725. The examiner can normally be reached M-F 6AM-2:30PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/ Primary Examiner, Art Unit 1632