.DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendments, filed 3/30/2026, is acknowledged.
Claims 1-96, 99-101, 104, 111, 115, and 118 are cancelled.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, 119-126 are currently pending and are under examination.
Response to Amendment
Applicant has amended the claims to recite the elected species of first agent comprising the HCDR1-3 of SEQ ID NO: 4, 2, and 3 and the LCDR1-3 of SEQ ID NO: 7, 8, 9, respectively (claim 124).
Applicant’s amendment of claim 97 to include administration of the first and second agents in a subject as a method of expanding T-cells has obviated the previous 35 U.S.C. 103 rejection and nonstatutory double patenting rejections in the Office Action mailed on 12/31/2025. Specifically, the prior art teaches that administration of antibodies that bind to CD3 or TCRβ lead to depletion of T-cells in subjects (discussed below in the 35 U.S.C. 112(a) enablement rejection).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/30/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner in its entirety.
In view of the amendments and remarks filed on 3/30/2026, the following rejections remain.
Claim Objections
Claims 107, 108, and 112-114 are objected to under 37 CFR 1.75(c) because they are improper dependent claims since they fail to refer back to an earlier claim. Rather claims 107, 108, and 112-114 refer forward to a to a proceeding claim 15. 37 CFR 1.75(c) states: “(c) One or more claims may be presented in dependent form, referring back to and further limiting another claim or claims in the same application.”
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.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-125 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a new grounds of rejection necessitated by Applicant’s amendment.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, 119-123, and 125 encompass a genus of first agents with a partial structure at best and the function of “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds” comprising the VH and VL sequences recited in claim 97(i)-(iii).
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, 119-124 encompass a genus of second agents with a partial structure at best and the function of “competes with an OKT3 antibody or an SP34-2 and/or binds to an epitope that overlaps with an epitope to which the antibody binds the OKT3 antibody or an SP34-2”.
The instant specification discloses example of different anti-TCRβV agents are disclosed in Example 1 and Tables 1-5, which include the following antibody clones: H131, humanized BHM1709 (or TRVβ 6-5 v1), humanized BHM1710 (or TRVβ 6-5 v2), humanized H131-3, humanized H131 (Table 2), 16G8, humanized TM29, humanized 16G8 1-4 (Table 3), TM23, humanized TM23 (Table 4), MPB2D5, and humanized MPB2D5, CAS 1.1.3, humanized CAS 1.1.3, IMMU222, humanized IMMU222, REA1062, humanized REA1062, JOVI-3, humanized JOVI-3 S511, humanized S511, humanized SH11, MH3-2, humanized MH3-2, ZOE, humanized ZOE, BJ1465, humanized BJ1465, BL37.2, humanized BL37.2, IG125, and humanized IG125 (Table 5). Each of these species are antibodies that have specific structures (i.e., amino acid sequences, especially in the critical CDR regions required for binding) that give rise to the function of “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds” comprising the VH and VL sequences recited in claim 97(i)-(iii).
Two examples of anti-CD3 agents are disclosed in the instant specification as well, which are the antibody clones OKT3 and SP34-2 (Example 1 ). Both of these have specific structures (i.e., amino acid sequences, especially in the critical CDR regions required for binding) that give rise to the function of"anti-CD3".
However, there does not appear to be an adequate written description in the specification as-filed of the essential structural features that provide the recited function of “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds” comprising the VH and VL sequences recited in claim 97(i)-(iii) in the broadly claimed genus of first agents; or the essential structural features that provide the recited function of “competes with an OKT3 antibody or an SP34-2 and/or binds to an epitope that overlaps with an epitope to which the antibody binds the OKT3 antibody or an SP34-2” in the broadly claimed genus of second agents.
The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or U.S.C 112, ¶ 1 "Written Description" Requirement make clear that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.
The claims encompass broad genera of first and/or second agents with no recited structure, which includes antibody structures with the recited functions. Additionally, the instant specification only provided examples of antibody structures with the recited functions. The USPTO has released a Memo on the Clarification of Written Description Guidance for Claims Drawn to Antibodies and Status of 2008 Training Materials, 02/22/2018. See uspto.gov/sites/default/files/documents/amgen_22feb2018.pdf.
The Memo clarifies the applicability of USPTO guidance regarding the written description requirement of 35 U.S.C. § 112(a) concerning the written description requirement for claims drawn to antibodies, including the following.
“In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional”.
In contrast to applicant’s reliance of describe the epitope that other antibody structures bind to in providing a fully characterized antigen/specific epitope as well as claiming structural elements of the antigen, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed first and/or second agents (which binds TCRβV and CD3 respectively) to demonstrate possession. Also, see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017).
There is no evidence that knowledge of the chemical structure of an antigen gives the required kind of structure identifying information about the corresponding antibodies Applicants attempt to describe the invention by describing something that is not the invention: viz., the antigens to which the antibodies may bind. There nothing in the disclosure that describes the antibodies as required by the test set forth in Ariad.
However, the first and second agents are required to practice the invention. The specification fails to provide any specific structural or physical information so as to define a genus of antibodies having the desired therapeutic properties. Applicant is merely relying on the identification of PCSK9 as the antigen and the well-known structure of antibodies in general. However, the claims do not recite a general antibody, but an antibody having a specific desired activity. However, Federal Circuit clarification of the law of written description as it applies to antibodies. Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017).
The claims are directed to a genera of first and second agents that include antibodies. However, Federal Circuit clarification of the law of written description as it applies to antibodies. The U.S. Court of Appeals for the Federal Circuit (Federal Circuit) decided Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), which concerned adequate written description for claims drawn to antibodies. The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. § 112(a) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called "newly characterized antigen" test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. § 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the "newly characterized antigen" test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of a newly characterized antigen alone should not be considered adequate written description of a claimed antibody to that newly characterized antigen, even when preparation of such an antibody is routine and conventional.
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed first and second agents to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed classes of first and/or second agents and in the absence of sufficient disclosure of identifying characteristics for the broadly claimed classes of first agents that compete with and/or bind to the same or overlapping epitopes of the antibody structures recited in claim 97(i)-(iii); and the broadly claimed classes of second agents that compete with and/or bind to the same or overlapping epitopes of the OKT3 or SP34-2 antibody clones the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
The specification at best describes plan for making claimed first and second agents that compete with the claimed antibody structures and then identifying those that satisfy claim limitations, but a mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011).
The instant specification discloses about 30 examples of different anti-TCRβV antibodies, H131, humanized BHM1709 (or TRVβ 6-5 v1), humanized BHM1710 (or TRVβ 6-5 v2), humanized H131-3, humanized H131 (Table 2), 16G8, humanized TM29, humanized 16G8 1-4 (Table 3), TM23, humanized TM23 (Table 4), MPB2D5, and humanized MPB2D5, CAS 1.1.3, humanized CAS 1.1.3, IMMU222, humanized IMMU222, REA1062, humanized REA1062, JOVI-3, humanized JOVI-3 S511, humanized S511, humanized SH11, MH3-2, humanized MH3-2, ZOE, humanized ZOE, BJ1465, humanized BJ1465, BL37.2, humanized BL37.2, IG125, and humanized IG125 (Table 5). Each of these species are antibodies that have specific structures (i.e., amino acid sequences, especially in the critical CDR regions required for binding) that give rise to the function of “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds” comprising the VH and VL sequences recited in claim 97(i)-(iii).
Two examples of anti-CD3 agents are disclosed in the instant specification as well, OKT3 and SP34-2 (Example 1 ).
It is unlikely that first agents as broadly defined by the claims which may contain less that the full complement of CDRs from the heavy and light chain variable region of the anti-TCRβV antibodies discussed supra fused to the framework sequences; or second agents as broadly defined by the claims which may contain less that the full complement of CDRs from the heavy and light chain variable region of the anti-CD3 antibodies OKT3 or SP34-2 fused to the framework sequences, would have the required binding functions. The specification provides no direction or guidance regarding how to produce monoclonal antibodies as broadly defined by the claims. Undue experimentation would be required to produce the invention commensurate with the scope of the claims from the written disclosure alone. Further, the specification does not teach that a functional antibody can be obtained by replacing the CDR regions of an acceptor antibody with the less than all the 6 CDRs sequences of a donor antibody.
With respect to the recitation of an antibody which does not comprise all 6 CDRs, the Examiner directs Applicant's attention to the training material given by Bennett Celsa, Example 2: (Ab genus: modified CDR's) slides 34-40. Example 2 of the Training material (aipla.org/docs/default-source/committee-documents/bcp-files/2020/uspto-bcp-antibody-slides-final.pdf?sfvrsn=b377f2cc_0) which requires that the claims explicitly recite the binding antigen in addition to all 6 CDR regions for fulfillment of the written description requirements under § 112, 1. Slide 39 indicates that a claim encompasses antibodies with 6 intact CDRs as well as a subgenus of antibodies that encompass up to 10% variation (fragments and/or analogs) in the 6 CDRs lacks written description. Slide 40 provide the conclusion that, a single antibody species would not be deemed by one of skill in the art to be representative of a claim that defines an antibody that binds antigen X comprising at least 90% homology to the 6 CDR of the VH and VL chains.
Artisans are well aware that knowledge of a given antigen (for instance TCRβV or CD3) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al (J Mol Biol. 2003 Nov 14;334(1): 103-18) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the FICDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document). Similarly, Lloyd et al (Protein Eng Des Sel. 2009 Mar;22(3):159-68) teach that a large majority of VH/VL germline gene segments are used in the antibody response to an antigen, even when the antibodies were selected by antigen binding, as their sequencing studies revealed that out of 841 unselected and 5,044 selected antibodies, all but one of the 49 functional VH gene segments was observed (see entire document). Goel et al (J Immunol. 2004 Dec 15; 173(12):7358-67) disclose the synthesis of three mAbs that bind to the same short (12-mer) peptide and found that the sequences of these antibodies which bound the same epitope exhibited diverse V gene usage indicating their independent germline origin (see entire document). As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data such as that of Edwards et al. indicating the diversity of sequence bound in a population of antibodies that bind to a given antigen no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen. Indeed, Kanyavuz et al (Nat Rev Immunol. 2019 Jun; 19(6):355-368) teach that “Theoretically, under physiological conditions, the human immune system can generate BCRs with 1026 distinct sequences, an astronomical number that is far greater than the calculated number of all B cell clones that can be generated during the lifespan of a healthy human (estimated to be 4 x 1014).
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of anti-TMPRSS6 antibodies or antigen binding fragments thereof falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-125 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
It is recommended to amend claim 97 to recite specific structure (for example, antibody structures defined by the amino acid sequences in the 6CDRs critical for antigen binding) for each of the first agent (which binds TCRβ V6 subunit) and second agent (which binds CD3) to resolve this issue.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is a new grounds of rejection necessitated by Applicant’s amendment.
It is apparent that the hybridoma that produce the OKT3 and SP34-2 antibodies are required to practice the claimed invention. See claim 97. As a required element, it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification. If it is not so obtainable or available, the enablement requirements of 35 USC 112, a deposit of the hybridoma, which produces this antibody, may satisfy first paragraph. See 37 CFR 1.801-1.809.
If the deposit has been made under the terms of the Budapest Treaty, an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the hybridoma has been deposited under the Budapest Treaty and that the hybridoma will be irrevocably and without restriction or condition released to the public upon the issuance of a patent would satisfy the deposit requirement made herein. See 37 CFR 1.808. Further, the record must be clear that the deposit will be maintained in a public depository for a period of 30 years after the date of deposit or 5 years after the last request for a sample or for the enforceable life of the patent whichever is longer. See 37 CFR 1.806. If the deposit has not been made under the Budapest treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature must be made, stating that the deposit has been made at an acceptable depository and that the criteria set forth in 37 CFR 1.801-1.809, have been met.
If the deposit was made after the effective filing date of the application for a patent in the United States, a verified statement is required from a person in a position to corroborate that the hybridoma described in the specification as filed are the same as that deposited in the depository. Corroboration may take the form of a showing of a chain of custody from applicant to the depository coupled with corroboration that the deposit is identical to the biological material described in the specification and in the applicant’s possession at the time the application was filed.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126 are 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 specific structures of first agents with the functions of “binds to the TCRβV region of the αβ TCR” and “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds”, second agents with the functions of “anti-CD3” and “competes with an OKT3 antibody or an SP34-2 and/or binds to an epitope that overlaps with an epitope to which the antibody binds the OKT3 antibody or an SP34-2”; does not reasonably provide enablement for a broad genus of first agents with no recited structure and the functions of “binds to the TCRβV region of the αβ TCR” and “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds” (claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, 119-123, and 125), a broad genus of second agents with no recited structure and the functions of “anti-CD3” and “competes with an OKT3 antibody or an SP34-2 and/or binds to an epitope that overlaps with an epitope to which the antibody binds the OKT3 antibody or an SP34-2” (claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, 119-124), including methods comprising administration of the first and second agent to a subject (claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126). 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 use the invention commensurate in scope with these claims. This is a new grounds of rejection necessitated by applicant’s amendments.
The claims are rejected under 35 U.S.C. 112(a) enablement for the same reasons discussed in the Office Action mailed on 12/31/2025. Briefly, the instant specification does not enable one with ordinary skill in the art to make and use first and second agent structures other than the antibody structures disclosed with the functions of “binds to the TCRβV region of the αβ TCR” and “competes with an antibody and/or binds to an epitope that overlaps with an epitope to which the antibody binds”, or with the functions of “anti-CD3” and “competes with an OKT3 antibody or an SP34-2 and/or binds to an epitope that overlaps with an epitope to which the antibody binds the OKT3 antibody or an SP34-2”.
The instant specification discloses the following anti-TCRβV antibody structures: H131, humanized BHM1709 (or TRVβ 6-5 v1), humanized BHM1710 (or TRVβ 6-5 v2), humanized H131-3, humanized H131 (Table 2), 16G8, humanized TM29, humanized 16G8 1-4 (Table 3), TM23, humanized TM23 (Table 4), MPB2D5, and humanized MPB2D5, CAS 1.1.3, humanized CAS 1.1.3, IMMU222, humanized IMMU222, REA1062, humanized REA1062, JOVI-3, humanized JOVI-3 S511, humanized S511, humanized SH11, MH3-2, humanized MH3-2, ZOE, humanized ZOE, BJ1465, humanized BJ1465, BL37.2, humanized BL37.2, IG125, and humanized IG125 (Table 5).
The instant specification additionally discloses the following anti-CD3 antibody structures: OKT3 and SP34-2 (Example 1).
Applicant has amended claim 97 to recite additional functional language, including that the first agent competes with one of the antibody structures recited in claim 97(i)-(iii), and the second agent competes with OKT3 or SP34-2. Applicant argues that these amendments obviate the rejection (Remarks pg. 11). However, the claims still recite broad genera of first and second agents with a partial structure at best and the recited functions, which encompasses “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all of the CDR regions that are necessary for antigen binding in the case of antibodies) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate agent/antibody, to determine whether it met the functional limitations recited in the claims. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
Additionally, regarding the claimed methods of expanding T-cells (claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126), Applicant has disclosed one method of contacting T cells in vitro, first with the “anti TCRβV antibody”, whose amino acid sequence is not readily apparent, followed by contacting the same cells with immobilized anti-CD3 antibody OKT3 (Example 2): “[h]ealthy donor PBMCs or purified T cells were first activated ex vivo with anti-TCRβV antibody for 5 days with plate-bound antibodies… Following primary stimulation, plate-bound anti-TCRβV antibody or anti-CD3e antibody (OKT3) were used to re-stimulate human PBMCs…”. No methods of administration of an anti-TCRβV and an anti-CD3 antibody in a subject were disclosed.
The instant claims have been amended to recite the method of expanding T-cells wherein the first and second agents are administered to a subject (claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-125), the instant specification disclosed only one working example of a method of expanding T cells comprising contacting T cells in vitro with the anti-TCRβV antibody clone “anti TCRβV antibody”, followed by contacting the cells with the anti-CD3 clone OKT3.
No working examples of methods of administering an anti-TCRβV antibody and an anti-CD3 antibody in a subject are disclosed, let alone an additional administration of adoptive T-cells expressing a CAR (claims 108, 120, 121).
Additionally, Gaston et al. (Kidney Int. 1991 Jan;39(1):141-8. doi: 10.1038/ki.1991.18) teaches that administration of the OKT3 antibody, the only disclosed anti-CD3 antibody used in a method of treatment comprising administration of an anti-TCR first agent and an anti-CD3 second agent (i.e., claim 118), will deplete T-cells from patients (Introduction, emphasis added): “OKT3 monoclonal antibody (mAb), introduced clinically in 1986, has been a significant addition to the immunosuppressive armamentarium, gaining widespread acceptance for both prophylaxis and therapy of acute rejection in solid organ transplant recipients. Its efficacy derives from a unique ability to modulate the CD34 portion of the of the T cell antigen receptor (TCR) complex, deleting it from the membrane of T lymphocytes, thus rendering the cells immunologically impotent. This effect accompanied by opsonization of CD3+ cells, with the subsequent removal by the reticuloendothelial system.”
Parlevliet et al. (Clin Exp Immunol. 1995 Feb;99(2):155-9. doi: 10.1111/j.1365-2249.1995.tb05526.x.) further teaches a study in which 38 renal transplant patients received a course of anti-CD3 monoclonal antibodies, including OKT3, T3.A, and T3.G2a (pg. 153, “Patients” Section). Anti-CD3 monoclonal antibody administration resulted in decreased proliferation of T-cells (pg. 157): “[i]n vivo, during treatment with OKT3 either 1 or 5mg daily, or with T3.G2a, lymphocyte response to PHA as measured with the whole-blood culture technique was significantly reduced.”
Miyahara et al. (Am J Transplant. 2012 Jun;12(6):1409-18. doi: 10.1111/j.1600-6143.2012.04006.x. Epub 2012 Mar 15) teaches administration of monoclonal antibodies specific for TCRβ, such as H57-597 (abstract), leads to the death and depletion of T-cells (Results and Fig. 1, emphasis added): “[b]ecause H57–597 mAb reduced the numbers of CD4+ cells by ∼60% and CD8+ cells by ∼40% (Figure 1D), it is possible that the Treg enrichment resulted from the anti-TCRb mAb-induced death of conventional T cells but not Treg cells. To test this possibility, we used Bcl-2 Tg mice in which conventional T cells are resistant to apoptosis (26). In contrast to the WT B6 mice, H57–597 mAb failed to reduce T cell numbers (Figure 1E) and consequently did not increase the frequency of Treg cells in Bcl-2 Tg mice (Figure 1F, left two panels). Thus, Treg cells in B6 mice were relatively resistant to H57–597 mAb-induced death compared to conventional T cells.”
Kanagawa (J Exp Med. 1989 Nov 1;170(5):1513-9. doi: 10.1084/jem.170.5.1513) additionally teaches that two monoclonal antibodies targeting TCR-Vβ6 (i.e., the TCR epitope recited in instant claim 97) deplete T-cells in vivo (Tables 1 and 2, pg. 1515-1516, emphasis added): “[f]low cytometric analysis of nylon wool nonadherent spleen cells from mice treated with anti-Vβ6 mAb, using anti-Vβ6 and anti-Vβ8 mAbs, indicated that the number of Vβ6+ treated T cells was greatly reduced…[t]hese data demonstrate that anti-Vβ6 mAb can eliminate Vβ6+ tumor cells as well as normal T cells that are Vβ6+…”
These teachings add further unpredictability to the claimed methods of expanding T cells, especially when administered in a subject (i.e., the invention encompassed by claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126), as the prior art teaches that administration of certain antibodies that bind to either TCRβ or CD3 into a subject can lead to the depletion of T-cells instead of the expansion.
Undue experimentation would be required by one with ordinary skill in the art to determine which species of compounds in the broadly claimed genre of compounds with no recited structure and the function of “binds to TCRβV” or “anti-CD3” would be able to successfully expand T cells, either in vitro or in vivo. Additionally, there is further unpredictability as to whether or not administration an anti-CD3 second agent to a subject, such as the disclosed example of OKT3, would lead to the function of “expanding T cells” in the subject.
The specification does not reasonably provide enablement to make and use the invention of instant claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126. The specification does enable one with ordinary skill to make the antibody clones and the method of expanding T cells in vitro discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed 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.
Claims 97, 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 97, 125, and 126 are indefinite in the recitation of "OKT3” and “SP34-2” because the characteristics are not known. The use of "OKT3” and “SP34-2” monoclonal antibodies as the sole means of identifying the claimed antibody and hybridoma renders the claim indefinite because "OKT3” and “SP34-2” are merely laboratory designations which does not clearly define the claimed product, since different laboratories may use the same laboratory designation s to define completely distinct hybridomas or cell lines. Dependent claims 98, 102, 103, 105-110, 112-114, 116, 117, and 119-126 no not resolve this issue and are also rejected as indefinite. It is recommended to recite the antibody structural elements of the OKT3 and SP34-2 (i.e., the amino acid sequences of the 6CDRs or VH/VL sequences) instead of the laboratory designations to resolve this issue.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEC JON PETERS whose telephone number is (703)756-5794. The examiner can normally be reached Monday-Friday 8:30am - 6:00pm EST.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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