DETAILED ACTION
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 election of OX40 agonist tavolixizumab as the species of TNFRSF agonist, in the reply filed on 8/11/25 is acknowledged. Upon reconsideration, 4-1BB antibody agonists are being included in the examination. Claims 73-74, 77-89 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected species.
Claims 68, 70-72, 75-76, and 90 are being acted upon.
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 68, 70-72, 75-76, and 90 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.
Claim 68 is indefinite in the recitation of a culture medium comprising OKT-3 (anti-CD3 antibody). Specifically, it is unclear whether the parenthetical recitation of anti-CD3 would encompass using any anti-CD3 antibody, or whether the claims require using the specific species OKT-3. The instant specification in paragraph 736 defines OKT-3 to refer to a monoclonal antibody or variant directed against CD3, and includes commercially available forms such as OKT-3. Thus, it appears that the claims are intended to encompass any anti-CD3 antibody, and for the purposes of examination, the claims are being interpreted to encompass any anti-CD3. Amendment to recite anti-CD3 antibody would be remedial.
Claims 72 and 76 are indefinite in the recitation of a “biosimilar”. The specification defines the term as being highly similar to a reference biological production. However, what is considered “highly similar” is unclear and indefinite (since highly and similar are relevant terms). The metes and bounds of the claimed biosimilar cannot be established.
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 72, 76, and 90 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 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, there is insufficient written description to demonstrate that applicant was in possession of the claimed genus of fragments, derivatives, variants, and biosimilars.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by 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 instant claims are directed to a method expanding TIL or a method of expanding TIL and treating cancer employing 4-1BB or OX40 monoclonal antibodies, such as or any fragment, variant, derivative or biosimilar thereof. The claims encompass methods employing a broad genus of structurally different agonists antibodies. For example, the claims would encompass variants of a genus of different monoclonal antibodies, such as variants of urelumab, with any number of amino acid differences, including in the CDR sequences. The claims would encompass a genus of fragments comprising a single domain of said antibodies, for example. The state of the art is such that the 6 CDRs of an antibody are critically involved in antigen binding, that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Rabia, 2018). The instant specification does not specifically disclose any specific variants, fragments, derivative, or biosimilar of the recited monoclonal antibody species. The specification does not disclose a correlation between the structure of said antibodies or agonists and agonist function.
The instant application has not provided a sufficient description showing possession of the necessary 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 of antibodies and inhibitors encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. §112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe Inc, 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002).
In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 43 USPQ2d 1398 (Fed Cir. 1997)).
The Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species; then the Requirement may be alternatively met by 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.
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.)
Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., lnc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning – i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also ensures that when a patent claims a genus by function, the specification recites sufficient materials to accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3. Note the following Court Decisions regarding the written description of antibodies in the context of the current claims.
In the absence of sufficient disclosure of relevant identifying characteristics, 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) and the specification at best describes plan for making variants, derivatives, fragments, or biosimilars with the “limitations above” and then identifying those that satisfy claim limitations, but mere “wish or plan” for obtaining claimed invention is not sufficient. Centocor Ortho Biotech Inc. v. Abbott Laboratories, 97 USPQ2d 1870 (Fed. Cir. 2011). There is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed variants, derivatives, fragments, or biosimilars to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claim 70 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
The specification and the claims as originally filed do not provide support for the invention as now claimed, specifically:
A process for preparation of TIL with a cell culture medium comprising a TNFRSF agonist, wherein the TNFRSF agonist is a “CD40 agonist”.
The specification in the background section in paragraph 10 discloses that CD40 is a TNFRSF agonist. However, the specification does not disclose using a CD40 agonist in the claimed method or preparing TIL. The only species of TNFRSF agonist contemplated are 4-1BB agonist, an OX40 agonist, a CD27 agonist, a GITR agonist, a HVEM agonist and a CD95 agonist (see paragraph 16).
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.
Claim(s) 68, 70-72, 75 and 90 is/are rejected under 35 U.S.C. 102(a)(1) as anticipated by WO2015/157636, as evidenced by Croft, 2010.
WO2015/157636 teaches a method of adoptive cell therapy for treating a patient with cancer comprising culturing a TIL population in a culture medium containing IL-2 and a 4-1BB agonist (i.e. a TNFRSF agonist) to expand TIL, and proving a second rapid expansion in a culture medium comprising anti-CD3, PBMC, IL-2, harvesting the TIL and harvesting the expanded TIL (see page 2, 9-11, Figure 11, in particular). WO2015/157636 teaches using OKT3 as the anti-CD3 (see page 10, in particular). WO2015/157636 teaches that the first culture is performed for 3 weeks (i.e. 21 days, see page 28, in particular). WO2015/157636 teaches performing the second culture period for 2 weeks (see page 29, in particular). WO2015/157636 teaches 4-1BB antibody BMS 663513 (i.e. urelumab) as the TNFRSF agonist (see page 28, in particular).
Regarding claim 75, as evidenced by Croft, OX40L (i.e. an OX40 agonist) is expressed by a variety of lymphocytes such as B cells, activated T cells, and also on antigen presenting cells, and in particular is expressed on TIL cells (see pages 58-59 and Table 1, in particular). Therefore, OX40L (i.e. an OX40 agonist) would inherently be present on at least some cell types of the TIL in the first culture step.
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.
Claim 68, 70-72, 75-76, and 90 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2015/157636, in view of US20030170238, Lee, 2004, and WO2016057841.
The teachings of WO2015/157636 are described above. WO2015/157636 also teaches that generating optimal killer CD8 T cell responses requires co-stimulation, that can be provided via ligation of TNF family members, including OX40 and 4-1BB. WO2015/157636 teaches that OX40 is of particular interest as an agonist anti-OX40 monoclonal antibody augments T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity (see pages 23-24, in particular). WO2015/157636 also teaches that both OX40 and 4-1BB are expressing by freshly isolated TIL (see page 18, in particular).
The reference differs from the claimed invention in that it does not explicitly teach including an OX40 agonist antibody in the first culture.
Lee et al. teach that 4-1BB and OX40 dual co-stimulation synergistically stimulates CD8 T cell clonal expansion and robust effector function (see page 3002, in particular). Lee teach anti-OX40 antibody as an OX40 agonist.
The ‘272 publication teaches methods of culturing T cells for immunotherapy, including TILs, and teaches that T cells can be activated using a variety of monoclonal antibodies that activate costimulatory molecules, used singly or in combination, and particularly teaches using antibodies that interact with OX40 (see entire document, paragraph 98, in particular).
WO2016057841 teaches OX40 agonist antibodies include MED10562, which is a humanized monoclonal antibody (see paragraph 528, in particular).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to include an anti-OX40 agonist antibody, as taught by Lee and the ‘272 publication, in the TIL cultures of WO2015/157636. The ordinary artisan at the time the invention was made would have been motivated to do so since the references teach that OX40L agonist antibody augments CD8 expansion and effector function, and that combined OX40 plus 4-1BB co-stimulation synergistically enhances CD8 T cell expansion, survival, and effector function. The ordinary artisan would have a reasonable expectation of success in including OX40L antibody, since WO2015/157636 specifically teaches that it is expressed by TIL, acts as a costimulatory molecule, and that anti-OX40 antibody can augment T cell differentiation and cytolytic function leading to enhanced anti-tumor immunity. See also the ‘272 publication which teaches that T cells cultured for immunotherapy, including TILs can be activated using monoclonal antibodies that OX40. Regarding claim 76, it is noted that any OX40 agonist monoclonal antibody, as taught by the cited reference, could be consider a ““variant” of the antibodies recited in the present claims. Additionally, WO2016057841 teaches OX40 agonist antibody MED10562 (i.e. tavolixizumab) is a known humanized OX40 agonist antibody. It would have been obvious to select from known available anti-OX40 antibodies, since doing so would involve choosing among a finite number of predictable options which could be pursued with a reasonable expectation of success. A person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense (see KSR International Co. V. Telefex Inc 82 USPQ2d 1385).
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claim 68, 70-72, 75-76, and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 65, 68-76, 82-98 of copending Application No. 17/050,552 (reference application), of claims 1-214 of 19/544,953, in view of WO2015/157636, US20030170238, Lee, 2004, and WO2016057841.Although the claims at issue are not identical, they are not patentably distinct from each other because the applications claim a method of treating a subject with cancer comprising expanding TIL with a first expansion with IL-2 for 3-14 days and a second rapid expansion with IL-2, OKT-3, and antigen presenting cells for 7-14 days, and administering the TIL. The applications claims PBMCs as APCs, including a 4-1BB agonist and/or OX40 agonist during the first expansion. Selecting 4-1BB and OX40 agonist antibodies would be obvious based on the teachings of WO2015/157636 US20030170238, Lee, 2004, and WO2016057841 for the same reasons et forth above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 68, 70-72, 75-76, and 90 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11083752, 10517894, 11026974, 11058758, 10130659, 10166257, 10272113, 10363273, 10398734, 10420799, 10463697, 10639330, 10646517, 10695372, 10894063, 10925900, 11007225, 11026974, 11007226, 11013770, 11040070, 11052116, 11052115, 11357841, 11384337, 11401507, 11541077, 11865140, 11998568, 11529372, 11713446, 12104172, 12024748, 12226434, 12031157, 12188048, 11975028, 11969444, 11857573, 12495791, 12629356, 12194061, 12558375, 12642816, 12622927, 12611429, 12636318,12485145, 11517592,11369637, 11364266, 11351199, 11344581, 11266694, 11344580, 11351198, 11351197, 11311578, 11337998, 11344579, 11291687, 11273181, 11304980, 11304,979, 11273180, 11202804, 11241456, 11241456, 11202803, 11141438, 11123371, 11179419, 11058728 in view of WO2015/157636, in view of US20030170238, Lee, 2004, and WO2016057841.
The issue patents all claim TIL for treating cancer, or methods of making TIL for a subject with cancer, wherein the TIL are produced by a process comprising expanding TIL by obtaining TILs by a first expansion with IL-2 and a second rapid expansion with IL-2, OKT-3, and antigen presenting cells. The patents claim PBMCs as APCs. The issued patents either claim culture timeframes within the scope of the instant claims, or alternatively such timeframes would be obvious based on the teachings of WO2015/157636. Furthermore, including a 41BB and/or OX40 agonist would be obvious over WO2015/157636, US20030170238, Lee, 2004, and WO2016057841 for the same reasons set forth above.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY E JUEDES whose telephone number is (571)272-4471. The examiner can normally be reached on M-F 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel Kolker can be reached on 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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