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 .
The claim listing filed May 14, 2026 is pending.
Claims 7, 9-19, 21, 22, 24-31, 33-35, 38-49, 51-75, 77-79, and 81-85 are canceled.
Claims 1-6, 8, 20, 23, 32, 36-37, 50, 76, 80, and 86-88 are pending.
Claims 2, 4-6, and 23 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions.
Claims 1, 3, 8, 20, 32, 36-37, 50, 76, 80, and 86-88 are currently under consideration.
Claim 1 is an independent claim.
Declaration Under 37 C.F.R. § 1.132
The declaration under 37 CFR 1.132 filed May 14, 2026 is sufficient to overcome the rejection of claims 1, 3, 8, 20, 32, 36-37, 50, 76, 80, and 86-88 based upon Bobbin et al. 2021 (“TIM-4-Chimeric Engulfment Receptor (CER) T Cells Elicit Phosphatidylserine-Dependent Cytotoxic and Innate-Like Function and Synergize with Approved PARP Inhibitors in an Ovarian Cancer Model.” Poster M195 presented at the American Society of Gene and Cell Therapy 25th Annual Meeting, May 16-20, 2021) applied under 35 U.S.C. 102(a)(1) and 103.
The declaration by Brandon Cieniewicz, Senior Director at Cero Therapeutics Holdings, Inc., which is the Applicant for U.S. Patent Application No. 18/041,200, was filed to correct the presentation date of Bobbin et al. Dr. Cieniewicz declares that the "May 2021" date listed on the Bobbin poster contains an inadvertent typographical error, and should read "May 2022." Dr. Cieniewicz is a co-author of the Bobbin poster. Dr. Cieniewicz declares that the Bobbin poster was presented at the American Society of Gene and Cell Therapy (ASGCT) 25th Annual Meeting, which was held May 16-19, 2022. Dr. Cieniewicz declares that a press release dated May 2, 2022 (submitted herewith as Appendix B) also confirms that the Bobbin poster was to be presented at the 25th Annual Meeting of the ASGCT on May 16, 2022.
In view of Dr. Cieniewicz’s declaration and the abstract and press release of Appendix A and B, respectively, the rejections under 35 U.S.C. 102(a)(1) and 103 over Bobbin et al. have been withdrawn.
The declaration under 37 CFR 1.132 filed May 14, 2026 is insufficient to overcome the rejection of claims 1, 3, 8, 20, 32, 36-37, 50, 76, and 86-88 based upon the teachings of Sun et al. 2017 (WO2018064076, an IDS reference filed 06/12/2025) in view of Heo and Duggan 2018 (Targeted Oncol. 13:533–539, a reference of record) and Lai et al. 2018 (Leukemia 32, 801–808, a reference of record) as applied under 35 U.S.C. 103 because the results presented by the Applicant in the declaration were not unexpected. See Examiner’s response to the Applicant’s arguments under 35 U.S.C. 103 below.
In the declaration by Brandon Cieniewicz, Senior Director at Cero Therapeutics Holdings, Inc., which is the Applicant for U.S. Patent Application No. 18/041,200, Dr. Cieniewicz declares that it is his opinion that the presently claimed combination therapy methods demonstrate unexpected results that could not have been predicted by a skilled scientist based upon the disclosure of Drew, Hudecek, Corey, Heo, and Lai.
Dr. Cieniewicz declares that example 4 of the present application provides a study of the cytotoxic activity of chimeric engulfment receptor (CER)-T cells and a PARP inhibitor. T cells modified with a CER comprising a Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3 signaling domain combined with a representative PARP inhibitor niraparib demonstrated synergistic killing of two ovarian cancer cell lines, one with and one without BRCA gene expression. Another experiment confirmed the synergistic activity of T cells modified with a CER comprising a Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3 signaling domain and niraparib against A2780 ovarian cancer cells, and demonstrated synergistic killing of CER-T cells combined with other PARP inhibitors, olaparib or rucaparib.
Dr. Cieniewicz also declares that a post-filing date study demonstrated that the addition of the TLR2 signaling domain to a CER construct comprising a Tim4 binding domain, a CD28 signaling domain, and a CD3 signaling domain unexpectedly enhanced cytotoxicity and cytokine production of the CER- T cells when administered in combination with a PARP inhibitor. Combination of the tested CERs with niraparib or olaparib exhibited synergistic cell killing activity as compared to CER monotherapy or PARP inhibitor monotherapy. Notably, the addition of the TLR2 signaling domain to the CER constructs conferred superior cytotoxicity. Furthermore, co-culture of A2780 ovarian cancer cells with a combination of T cells modified with a CER construct containing a TLR2 signaling domain and a PARP inhibitor (niraparib or olaparib) resulted in enhanced secretion of activating cytokines (IFNγ and TNFα) compared to a CER construct lacking the TLR2 signaling domain. Addition of TLR2 signaling domain did not enhance granzyme B production.
Dr. Cieniewicz further declares that another post-filing date study demonstrated that a combination comprising T cells engineered to express a representative CER according to the present claims and a PARP inhibitor exhibited unexpectedly enhanced killing of A2780 ovarian cancer cells in vitro compared to CER monotherapy or PARP inhibitor monotherapy.
In summary, Dr. Cieniewicz declares that their studies demonstrate that the claimed combination-an engineered T cell comprising a CER comprising a wildtype Tim4 binding domain, a CD28 signaling domain, a CD3 signaling domain, and a TLR2 signaling domain, combined with a PARP inhibitor-possessed enhanced cytotoxic activity towards ovarian cancer cells and induced enhanced inflammatory cytokine production. Dr. Cieniewicz declares that the enhanced cytotoxicity and cytokine production conferred by the addition of the TLR2 signaling domain to the CD28 signaling domain and CD3 signaling domain of the CER recited in the claimed combination therapy are not taught or suggested by the cited references. None of the cited references teach or suggest that the addition of a TLR2 signaling domain to a CER comprising a Tim4 binding domain, a CD28 signaling domain, and a CD3 signaling domain would enhance cytotoxicity or cytokine production when administered in combination with a PARP inhibitor to ovarian cancer cells. It is Dr. Cieniewicz’s opinion that these findings were surprising and would not have been obvious to one having ordinary skill in the art at the time of the invention in view of the cited references.
In response to Dr. Cieniewicz’s declaration, the Examiner notes that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP 2143.02.I.
Therefore, while the Examiner agrees that the Applicant has demonstrated that the claimed therapeutic combination has enhanced and synergistic anti-tumor cell activity and cytokine production when compared to monotherapy with either agent, the Examiner still maintains that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Sun et al. to incorporate the teachings of Heo and Duggan and Lai et al. to include that Sun et al.’s CER01+ T cells are used to treat ovarian cancer in combination with a PARP inhibitor. The Examiner maintains that in view of the combined reference teachings, a skilled artisan would have reasonably expected that claimed combination would lead to expectedly enhanced and synergistic anti-tumor cell activity. See Examiner’s response to the Applicant’s arguments under 35 U.S.C. 103 below.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Terminal Disclaimer
In view of the terminal disclaimers filed May 14, 2026, the nonstatutory double patenting rejections over the claims in co-pending Applications 19/019,111 and 18/041,195 have been withdrawn.
In view of the Applicant’s amendment, remarks, declaration, and terminal disclaimers filed May 14, 2026, the following rejections are set forth.
Priority
Applicant's domestic benefit claims to the provisional applications 63/066,150, 63/087,049, and 63/226,712 is acknowledged. However, the provisional applications 63/066,150 (filed August 14, 2020) and 63/087,049 (filed October 2, 2020) upon which priorities are claimed fail to provide adequate support under 35 U.S.C. 112(a) for claims 1-6, 8, 20, 23, 32, 36-37, 50, 76, 80, and 86-88 of this application.
Specifically, insufficient support was identified for the limitation of “the chimeric engulfment receptor comprising a TLR2 signaling domain” in these two provisional applications. Consequently, the claims have been accorded the priority of the filing date of the provisional application 63/226,712 on July 28, 2021.
Should Applicant disagree with the Examiner’s factual determination above, it is incumbent upon Applicant to provide a showing that specifically supports the instant claim limitations.
Claim Interpretation
Claim 76 recites “wherein the intracellular signaling domain comprises a primary intracellular signaling domain comprising a CD28 signaling domain; a secondary intracellular signaling domain comprising a CD3𝞯 signaling domain; and a tertiary intracellular signaling domain comprising a TLR2 signaling domain” in lines 5-8. The specification discloses that the designation of primary, secondary, and tertiary intracellular signaling domains includes, but is not limited to, the arrangement of the primary intracellular signaling domain at the N-terminus, secondary intracellular signaling domain in the middle, and tertiary intracellular signaling domain at the C-terminus of the intracellular portion of the chimeric Tim receptor (e.g. see page 62, lines 1-16).
Claim Rejections - 35 USC § 112
Indefinite Language
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.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 1, 3, 8, 20, 32, 36-37, 50, 76, 80, and 86-88 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 1 recites “a wildtype Tim4 binding domain” in line 8. It is unclear of the wildtype Tim4 binding domain is wildtype Tim4 or if it binds wildtype Tim4. Therefore, the claim is indefinite.
Amending claim 1 to recite “a wildtype Tim4 extracellular domain that binds to phosphatidylserine (PS)” would obviate this part of the rejection.
Claim 32 recites “wherein the Tim4 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:34 and/or the Tim4 mucin domain comprises the amino acid sequence set forth in SEQ ID NO:35” in lines 1-3. Claim 32 is dependent on claim 1 which does not recite “a Tim4 IgV domain” or “a Tim4 mucin domain.” Therefore, these limitations lack antecedent basis and render claim 32 indefinite.
Amending claim 32 to recite “wherein the wildtype Tim4 binding domain comprises a Tim4 IgV domain comprising the amino acid sequence set forth in SEQ ID NO:34 and/or a Tim4 mucin domain comprising the amino acid sequence set forth in SEQ ID NO:35” would obviate this part of the rejection.
Claim 76 recites “the CD28 signaling domain; the CD3𝞯 signaling domain; and the TLR2 signaling domain are arranged from N-terminus to C-terminus within the intracellular signaling domain” in lines 7-9. It is unclear which of these domains comes first in the N-terminus to C-terminus arrangement, thereby rendering the claim indefinite.
Amending claim 76 to recite “the CD28 signaling domain; the CD3𝞯 signaling domain; and the TLR2 signaling domain are arranged from N-terminus to C-terminus, respectively, within the intracellular signaling domain” would obviate this part of the rejection.
Written Description
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 1, 3, 8, 20, 32, 36-37, 50, 76, and 86-88 stand 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 contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are drawn to a method for treating ovarian cancer, the method comprising administering to the subject an effective amount of: (i) an engineered T cell comprising: a chimeric engulfment receptor comprising a single chain chimeric protein, the single chain chimeric protein comprising:(a) a wildtype Tim4 binding domain; (b) an intracellular signaling domain, wherein the intracellular signaling domain comprises a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain; and (c) a transmembrane domain positioned between and connecting the wildtype Tim4 binding domain and the intracellular signaling domain; and (ii) a Poly (ADP-ribose) polymerase (PARP) inhibitor.
To support such chimeric engulfment receptors (CERs), the Applicant discloses four species pCTX1162 (SEQ ID NO: 228), pCTX1163 (SEQ ID NO: 229), pCTX1173 (SEQ ID NO: 239), and pCTX1174 (SEQ ID NO: 240) (e.g. see Table 10, spanning pages 78-80). These species comprise a TIM4 extracellular domain (SEQ ID NO: 219) which comprises the human Tim4 binding domain (SEQ ID NO:2) (e.g. see page 12, lines 13-17). A Tim4 binding domain includes a variable immunoglobulin (IgV) like domain (referred to herein as an "IgV domain") and a Mucin like domain ("referred to herein as a "mucin domain") (e.g. see page 12, lines 18-20). An exemplary human Tim4 IgV domain comprises an amino acid sequence of SEQ ID NO:34, and an exemplary human Tim4 mucin domain comprises an amino acid sequence of SEQ ID NO:35 (e.g. see page 12, lines 20-22). The Applicant further discloses that the Tim4 binding domain may comprise or consist of amino acids 25-314 of SEQ ID NO:2 (e.g. see page 28, lines 6-22).
When given the broadest reasonable interpretation in light of specification, the Tim4-based CERs of the instant invention are defined broadly to be any CER that comprises a single chain chimeric protein comprising:(a) any wildtype Tim4 binding domain; (b) an intracellular signaling domain comprising a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain and (c) a transmembrane domain positioned between and connecting the wildtype Tim4 binding domain and the intracellular signaling domain.
It is noted that the broadest claim (claim 1) does not indicate any specific structure for the wildtype Tim4 binding domain or the genus of CERs claimed.
It further noted that claim 80 is the only claim that recites sufficient structure for the wildtype Tim4 binding domain.
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 (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
It is known that T cell immunoglobulin mucin (TIM) proteins regulate T cell activation and tolerance (e.g. see Kobayashi et al. 2007, Immunity 27, 927–940, a reference of record; abstract). TIM-4 is expressed on human and mouse macrophages and dendritic cells and specifically binds phosphatidylserine (PS) on the surface of apoptotic cells. TIM-4-transfected cells efficiently phagocytize apoptotic cells and mutations in the unique cavity of TIM-4 eliminates PS binding and phagocytosis (e.g. see abstract). All TIM family proteins are type I cell-surface glycoproteins and share common structural motifs including an immunoglobulin variable (IgV) domain with six cysteines, a mucin-like domain, a transmembrane domain, and a cytoplasmic domain (e.g. see page 927, paragraph spanning left and right columns). The IgV domain of TIM-4 displays a distinctive cleft formed by the CC′ and FG loops of the GFC β sheet (e.g. see page 927, right column, second paragraph). In TIM-4, the narrow cavity built by the CC′ and FG loops is a binding site for PS (e.g. see page 927, right column, second paragraph). Loss of any of the amino acids (119–122, WFND) that line this binding cavity eliminates binding to PS and phagocytosis (e.g. see page 936, left column, fourth paragraph).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the narrow binding cavity of the IgV of Tim4 which gives rise to the functional property of engulfment. The PS ligand to which said Tim4 binds, is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the narrow binding cavity of the IgV itself.
As noted above, the specification discloses four species of CERs that comprise a Tim4 binding domain, which include an IgV domain and a mucin domain, that may comprise or consist of SEQ ID NO:2 or amino acids 25-314 of SEQ ID NO:2. Such a disclosure does not serve to provide sufficient written description of the claimed genus of CERs comprising a wildtype Tim4 binding domain. As it is currently claimed, the CER of the instant invention comprises any wildtype sequence of the Tim4 binding domain, including truncated wildtype sequences lacking amino acids 119–122. However, it is known that loss of any of the amino acids 119–122 eliminates binding to PS and phagocytosis (i.e. engulfment).
Thus, it does not appear, based upon the limited disclosure of the four Tim4-based CERs alone, which only comprise the full length wildtype Tim4 binding domain of SEQ ID NO: 2, that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the entire genus of wildtype Tim4 binding domain-based CERs.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of wildtype Tim4 binding domain-based CERs encompassed by the claims at the time the instant application was filed.
Amending claim 1 to recite that that wildtype Tim4 binding domain comprises SEQ ID NO: 2 would obviate this part of the rejection.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 8, 20, 32, 36-37, 50, 76, and 86-88 stand rejected under 35 U.S.C. 103 as being unpatentable over Sun et al. 2017 (WO2018064076, an IDS reference filed 06/12/2025) in view of Heo and Duggan 2018 (Targeted Oncol. 13:533–539, a reference of record) and Lai et al. 2018 (Leukemia 32, 801–808, a reference of record).
In view of the Applicant’s election, independent claim 1 and dependent claim 3 are drawn to a method for treating ovarian cancer, the method comprising administering to the subject an effective amount of: (i) an engineered T cell comprising: a chimeric engulfment receptor comprising a single chain chimeric protein, the single chain chimeric protein comprising:(a) a wildtype Tim4 binding domain; (b) an intracellular signaling domain, wherein the intracellular signaling domain comprises a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain; and (c) a transmembrane domain positioned between and connecting the wildtype Tim4 binding domain and the intracellular signaling domain; and (ii) a Poly (ADP-ribose) polymerase (PARP) inhibitor.
Dependent claim 8 limits the PARP inhibitor to niraparib.
Dependent claim 20 limits the method to that which further comprises administering an additional therapeutic agent comprising immune checkpoint molecule inhibitor.
Dependent claim 32 limits the method of claim 32 to that wherein the Tim4 IgV domain comprises the amino acid sequence set forth in SEQ ID NO:34 and/or the Tim4 mucin domain comprises the amino acid sequence set forth in SEQ ID NO:35.
Dependent claims 36 and 37 limits the transmembrane domain to that which comprises a CD28 transmembrane domain. Dependent claim 37 further limits the CD28 transmembrane domain to that which comprises SEQ ID NO: 7.
Dependent claim 50, limits the CD28 signaling domain to that which comprises SEQ ID NO:4 or 26, the CD3𝞯 signaling domain to that which comprises SEQ ID NO:5, or the TLR2 signaling domain to that which comprises SEQ ID NO:222.
Dependent claim 76 limits the method of claim 1 to that wherein (a) the CD28 signaling domain; the CD3𝞯 signaling domain; and the TLR2 signaling domain are arranged from N-terminus to C-terminus within the intracellular signaling domain; and (b) the transmembrane domain is a CD28 transmembrane domain.
Dependent claim 86 limits the engineered T cell to a CD8+ T cell.
Dependent claim 87 limits the T cell to a human cell.
Dependent claim 88 limits the method to that wherein the engineered T cell is administered as a composition further comprising a pharmaceutically acceptable excipient.
Sun et al. teach the intravenous administration of T cells transduced with a chimeric engulfment receptor (CER): CER01 (SEQ ID NO: 71) for the treatment of B-cell lymphoma in mice in combination with low dose radiotherapy or chimeric antigen receptor (CAR) immunotherapy (e.g. see page 129, line 10 – page 130, line 2). CER01 comprises (a) the extracellular Tim4 binding domain which targets the pro-engulfment marker PS, (b) the intracellular MERTK engulfment signaling domain, and (c) the Tim4 transmembrane domain which is positioned between and connects the extracellular Tim4 binding domain and the intracellular MERTK engulfment signaling domain(e.g. see page 2, lines 9-29 and page 9, lines 22-25). CER01+ T cells targeting phosphatidylserine synergized with low dose radiotherapy and low dose CAR modified T cell therapy (e.g. see page 129, line 10 – page 130, line 2). Sun et al. teach that the T cells may include CD8+ T cells and may be derived from human (e.g. see page 67, lines 8-12). It is noted that Sun et al. teach pharmaceutical compositions comprising their CER modified cells and a pharmaceutically excipient (e.g. see page 77, lines 14 and 15).
It is noted that SEQ ID NO: 71 comprises instant SEQ ID NO: 24, the murine Tim4 binding domain, see sequence alignment below.
Phagocytosis of damaged, self-derived apoptotic cells or cell debris (e.g., efferocytosis) is typically a non-inflammatory process (e.g. see page 1, lines 20-33). Billions of damaged, dying, and unwanted cells undergo apoptosis each day. Unwanted cells include cells irreversibly damaged by cytotoxic agents. Steps for apoptotic cell clearance include: (1) release of "find me" signals from apoptotic cells to recruit phagocytes to the location of apoptotic cells; (2) "eat me" signals exposed on the surface of apoptotic cells are bound by phagocytes via specific receptors; (3) cytoskeletal rearrangement to engulf the apoptotic cell; and (4) the ingested apoptotic cell is digested and specific phagocytic responses are elicited (e.g., secretion of anti-inflammatory cytokines) (e.g. see page 1, lines 20-33).
There is an ongoing need for new compositions and methods of treating various cancers by enhancing the removal of apoptotic, damaged, or necrotic cells from the body that have been affected by cytotoxic treatments (e.g. see page 2, lines 1-6). CER01+ T cells use the extracellular domain of T cell immunoglobulin and mucin domain 4 (Tim4) to direct phagocytic removal of apoptotic cells that are damaged by cytotoxic radio- and immune-therapy treatment in a phosphatidylserine (PS)-dependent manner. PS is known as a pro-engulfment marker or “eat me” signal (e.g. see page 31, lines 3-16).
Sun et al. also teach that the CERs may be designed to generate an inflammatory response to a target cell/organ/tissue/area (e.g. see page 2, lines 9-29). While apoptotic cell clearance is typically a non-inflammatory process, inflammation can be beneficial to the host in certain contexts, such as, for example, in the context clearance of apoptotic tumor cells to induce an immune response to residual tumor cells. The intracellular engulfment signaling domain of Sun et al.’s CERs may comprise a homeostatic engulfment domain and a pro-inflammatory engulfment domain or a primary engulfment signaling domain and a secondary engulfment signaling domain (e.g. see page 2, lines 9-29).
Sun et al. also teach that the transmembrane domain, which is positioned between and connects the extracellular domain and the engulfment signaling domain, may be a CD28 transmembrane domain of SEQ ID NO:68 (e.g. see claim 9) which is identical to instant SEQ ID NO: 7 (see sequence alignment below); and that the extracellular domain may comprise extracellular spacer domain positioned between and connecting the binding domain and transmembrane domain (e.g. see page 2, lines 9-29).
Sun et al. further teach that their CER modified cells can be administered to a subject in conjunction or combination with one or more additional therapies including chemotherapeutics and immune checkpoint molecule inhibitors (e.g. see page 78, lines 14-20), such as a cytotoxic agent or a DNA repair inhibitor (e.g. see page 80, lines 6-13). CER modified cells may clear apoptotic, dead, dying, damaged, infected, or necrotic cells displaying pro-apoptotic markers induced in the setting of the one or more additional therapies (e.g. see page 78, lines 22-24).
Sun et al. also teach a method of treating a subject with cancer comprising administering to the subject an effective amount of a cell genetically modified to express the CER (e.g. see claim 134). The cancer may include ovarian cancer (e.g. see page 29, line 7).
Sun et al. also teach that the Tim4 binding domain may comprise SEQ ID NO: 29, the human Tim4 binding domain, which comprises instant SEQ ID NOs: 34 and 35 (e.g. see claim 3). It is noted that while the CER01+ T cells comprise the murine Tim4 binding domain (SEQ ID NO: 71), they were used in a mouse model for treating lymphoma. However, it would be obvious to a skilled artisan to modify the CER01+ T cells to express the human Tim4 binding domain (SEQ ID NO: 29) instead, as is suggested by claim 3, if it is to be applied in a human because the human Tim4 binding domain would presumably be less immunogenic than the murine Tim4 binding domain.
Sequence alignment of Sun et al.’s SEQ ID NO: 71 and instant SEQ ID NO: 24:
Query Match 36.1%; Score 1460; DB 1; Length 279;
Best Local Similarity 100.0%;
Matches 279; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MSKGLLLLWLVTELWWLYLTPAASEDTIIGFLGQPVTLPCHYLSWSQSRNSMCWGKGSCP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MSKGLLLLWLVTELWWLYLTPAASEDTIIGFLGQPVTLPCHYLSWSQSRNSMCWGKGSCP 60
Qy 61 NSKCNAELLRTDGTRIISRKSTKYTLLGKVQFGEVSLTISNTNRGDSGVYCCRIEVPGWF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NSKCNAELLRTDGTRIISRKSTKYTLLGKVQFGEVSLTISNTNRGDSGVYCCRIEVPGWF 120
Qy 121 NDVKKNVRLELRRATTTKKPTTTTRPTTTPYVTTTTPELLPTTVMTTSVLPTTTPPQTLA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NDVKKNVRLELRRATTTKKPTTTTRPTTTPYVTTTTPELLPTTVMTTSVLPTTTPPQTLA 180
Qy 181 TTAFSTAVTTCPSTTPGSFSQETTKGSAFTTESETLPASNHSQRSMMTISTDIAVLRPTG 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 TTAFSTAVTTCPSTTPGSFSQETTKGSAFTTESETLPASNHSQRSMMTISTDIAVLRPTG 240
Qy 241 SNPGILPSTSQLTTQKTTLTTSESLQKTTKSHQINSRQT 279
|||||||||||||||||||||||||||||||||||||||
Db 241 SNPGILPSTSQLTTQKTTLTTSESLQKTTKSHQINSRQT 279
Sequence alignment of Sun et al.’s SEQ ID NO: 29 and instant SEQ ID NOs: 34 and 35:
Query Match 91.8%; Score 1515; DB 1; Length 290;
Best Local Similarity 100.0%;
Matches 290; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 25 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 84
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 ETVVTEVLGHRVTLPCLYSSWSHNSNSMCWGKDQCPYSGCKEALIRTDGMRVTSRKSAKY 60
Qy 85 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 144
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RLQGTIPRGDVSLTILNPSESDSGVYCCRIEVPGWFNDVKINVRLNLQRASTTTHRTATT 120
Qy 145 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 204
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TTRRTTTTSPTTTRQMTTTPAALPTTVVTTPDLTTGTPLQMTTIAVFTTANTCLSLTPST 180
Qy 205 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 264
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LPEEATGLLTPEPSKEGPILTAESETVLPSDSWSSVESTSADTVLLTSKESKVWDLPSTS 240
Qy 265 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 314
||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 HVSMWKTSDSVSSPQPGASDTAVPEQNKTTKTGQMDGIPMSMKNEMPISQ 290
Sequence alignment of Sun et al.’s SEQ ID NO: 68 and instant SEQ ID NO: 7:
Query Match 100.0%; Score 141; DB 1; Length 27;
Best Local Similarity 100.0%;
Matches 27; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 FWVLVVVGGVLACYSLLVTVAFIIFWV 27
|||||||||||||||||||||||||||
Db 1 FWVLVVVGGVLACYSLLVTVAFIIFWV 27
Sun et al. do not teach that their CER01+ T cells are used to treat ovarian cancer in combination with a Poly (ADP-ribose) polymerase (PARP) inhibitor or that the intracellular signaling domain of CER01 comprises a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain.
Heo and Duggan teach that niraparib (Zejula®), a poly (ADP-ribose) polymerase (PARP) inhibitor, is approved for the maintenance treatment of recurrent, epithelial ovarian, fallopian tube, or primary peritoneal cancer in patients who are in complete or partial response to platinum-based chemotherapy (e.g. see Abstract). Inhibition of PARP, an enzyme that is involved in single-stranded DNA break repair, has proven to be an effective treatment strategy in cancers that involve DNA repair mechanism defects (e.g. see paragraph spanning pages 533 and 534). These genetic aberrations, which can predispose women to hereditary ovarian cancer, are caused by specific mutations in DNA repair genes, including BRCA 1 and 2, leading to cellular homologous recombination deficiency (HRD). Targeting PARP inhibition in the presence of HRD results in genetic instability and cell death (or apoptosis) in a process known as ‘synthetic lethality’ (e.g. see paragraph spanning pages 533 and 534). The patients in Heo and Duggan’s study include those with advanced cancer (e.g. see page 534, right column, third paragraph).
Lai et al. teach that in chimeric antigen receptors (CARs), which have a similar design to Sun et al.’s CERs in that they comprise an extracellular target binding domain, a transmembrane domain, and intracellular signaling components, both CD3ζ signaling and costimulatory signaling domains are needed to generate effective CARs that provide the signals necessary for full activation, expansion, and survival of CAR T cells (e.g. see page 801, left column, first paragraph). The incorporation of the costimulatory molecule CD28 significantly improves the expansion, cytokine production, in vivo persistence and antitumor efficacy of CAR T cells (e.g. see page 801, left column, first paragraph). Lai et al. discovered that the addition of a TLR2 signaling domain in the intracellular signaling domain of a CAR that comprises CD3ζ and CD28, can generate more powerful CARs, which have superior antitumor efficacies in vitro and in vivo and can be used in patients (e.g. see page 806, right column, second paragraph). Lai et al.’s findings reveal an important new strategy for CAR design which bridges the conventional costimulation of adaptive immunity with unconventional innate immune signaling (e.g. see page 806, right column, second paragraph). It is noted that the amino acid sequences recited in claim 50 for the CD28 (SEQ ID NO: 4), CD3𝞯 (SEQ ID NO: 5), and TLR2 (SEQ ID NO: 222) signaling domains are the wildtype amino acid sequences. Therefore, while Lai et al. do not explicitly recite the amino acid sequences of these intracellular signaling domains, a skilled artisan would reasonably assume that the Lai et al.’s the CD28, CD3𝞯, and TLR2 intracellular signaling domains are the wildtype proteins and would necessarily have the same amino acids sequences as recited in instant claim 50, especially without evidence to the contrary.
It is further noted that Lai et al. teach the arrangement of the intracellular signaling domains, from N- to C-terminus, as CD28, CD3𝞯, and TLR2 (e.g. see page 802, left column, first paragraph and supplementary figure 1a, copied below) which is identical to that described for the primary, secondary, and tertiary signaling domains of claim 76 (see claim interpretation above). Figure 1a also shows a CD28 transmembrane domain.
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Supplementary Figure 1a from Lai et al. 2018 (Leukemia 32, 801–808)
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Sun et al. to incorporate the teachings of Heo and Duggan and Lai et al. to include that Sun et al.’s CER01+ T cells are used to treat ovarian cancer in combination with a PARP inhibitor and that the intracellular signaling domain of CER01 comprises a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain.
There is an ongoing need for new compositions and methods of treating various cancers by enhancing the removal of apoptotic, damaged, or necrotic cells from the body that have been affected by cytotoxic treatments (Sun et al.). Phagocytosis of damaged, apoptotic cells is typically a non-inflammatory process; however inflammation can be beneficial for clearing apoptotic tumor cells because it induces an immune response to residual tumor cells (Sun et al.). Tim4-based CER T-cells, which direct phagocytic removal of apoptotic cells in a PS-dependent manner, have been designed to generate this targeted inflammatory response (Sun et al.). PS is known as a pro-engulfment marker or “eat me” signal that is expressed on the surface of apoptotic cells (Sun et al.). Tim4-based CER T-cells display a synergistic anti-tumor effect with anti-cancer therapies (Sun et al.).
Given the known applications and synergistic effect of Tim4-based CER T-cells in combination with anti-cancer therapies; the applications of niraparib, a PARP (or DNA repair) inhibitor, for the treatment of ovarian cancer by apoptosis; and Sun et al.’s suggestion that their CER modified cells can be administered in combination with chemotherapies, including DNA repair inhibitors, to clear cells displaying pro-apoptotic markers as a result of chemotherapy; it would have been obvious to a skilled artisan, with the goal of improving the treatment of ovarian cancer with niraparib, which induces apoptosis, to apply Sun et al.’s Tim4-based CER T-cells in Heo and Duggan’s niraparib-based treatment method with a reasonable expectation of success. A skilled artisan would reasonably expect that the Tim4-based CER T-cells would have a synergistic effect with niraparib for treating ovarian cancer by clearing cells displaying pro-apoptotic markers, such as PS, as a result of niraparib therapy, especially in the absence of evidence to the contrary.
Furthermore, given that CERs have a similar design to CARs, in that they both comprise an extracellular target binding domain and intracellular signaling components; and that the activation, expansion, and survival of CAR T cells can be enhanced by incorporating CD3ζ, CD28, and TLR2 intracellular signaling domains into the CAR; it would have been obvious to a skilled artisan, with the goal of enhancing the activation, expansion, and survival of Sun et al.’s Tim4-based CER T-cells, to incorporate the CD3ζ, CD28, and TLR2 intracellular signaling domains into the intracellular domain of the CER with a reasonable expectation of success. Not only would an artisan reasonably expect, especially in the absence of evidence to the contrary, that the addition of these intracellular signaling domains into the CER would improve expansion and survival of the Tim4-based CER T-cells; but an artisan would also expect that the phagocytic capacity of the Tim4-based CER T-cells would be complemented by an additional cytotoxic capacity that is afforded by the CD3ζ, CD28, and TLR2 intracellular signaling domains. Moreover, complementing the phagocytic capacity of the Tim4-based CER T-cells with a cytotoxic capability could be further enhanced by specifically selecting CD8+ in which the CER can be expressed. It is well-known that CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), play a crucial role in the immune response by targeting and killing infected or malignant cells.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that the combined teachings of Corey, Heo, and Lai fail to establish a case of prima facie obviousness for the instantly claimed method. The Applicant argues that while Lai discloses these signaling domains in the context of a chimeric antigen receptor, nothing in Lai teaches or suggests incorporating them into a CER comprising a wildtype Tim4 binding domain. The Applicant further argues that the Examiner’s assertion that CERs have a similar design to CARs, and therefore a skilled artisan would reasonably expect that the phagocytic activity of the Tim4-based CER T cells would be complemented by inclusion of a CD28 signaling domain, a CD3𝞯 signaling and a TLR2 signaling domain fails to account for structural and functional differences between CERs and CARs.
The Applicant asserts that structurally, the CER binding domain recited in the claims (wildtype Tim4 binding domain) is derived from Tim4 receptor's ectodomain and targets phosphatidylserine-a lipid "eat me" signal on damaged cells. The Applicant further asserts that in contrast, the CAR binding domain of Lai is a scFv targeting CD19 or mesothelin-a tumor protein antigen. The Applicant argues that functionally, the CER confers phosphatidylserine-specific engulfment activity to the host T cell, a cell type that does not normally possess engulfment activity, whereas a CAR-T cell confers directed cytotoxicity driven by binding of the scFv to its cognate tumor antigen. The Applicant argues that none of the cited references teach or suggest that incorporation of any combination of CD28, CD3𝞯, and TLR2 signaling domains would confer engulfment phenotype in a CER construct. The Applicant asserts that, therefore, the combined teachings of Corey, Heo, and Lai fail to teach or suggest all of the limitations recited in the rejected claims, and also fail to provide one of ordinary skill in the art a reasonable expectation of success.
The Applicant also argues that even assuming arguendo a prima facie case of obviousness, the rejection is also improper in view of objective evidence of unexpected results. The Applicant asserts that the experimental data in the specification and post-filing date studies provide compelling evidence that use of the claimed combination led to unexpectedly enhanced anti-tumor cell activity and cytokine production that were not taught or suggested by the cited references. The Applicant asserts that example 4 of the present application provides experimental evidence that T cells engineered to express a CER comprising a Tim4 binding domain, a CD28 transmembrane domain, a CD28 signaling domain, and a CD3𝞯 signaling domain, when administered in combination with a representative PARP inhibitor niraparib exhibited synergistic killing of two ovarian cancer cell lines-A2780 (BRCA wild type) and Kuramochi (BRCA-deficient). The Applicant further asserts that the synergistic activity against A2780 cells extended to other PARP inhibitors, olaparib and rucaparib.
The Applicant further argues that a post-filing date study demonstrated that addition of the TLR2 signaling domain to the CER construct unexpectedly enhanced both cytotoxicity and cytokine production of the claimed combination. See Brandon Cieniewicz Declaration under 37 CFR § 1.132 submitted herewith (hereinafter "Cieniewicz Declaration"). The Cieniewicz Declaration states that T cells were engineered to express one of three CER constructs: (i) Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3𝞯 signaling domain (lacking a TLR2 signaling domain); (ii) Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3𝞯 signaling domain-TLR2 signaling domain; and (iii) Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-TLR2 signaling domain-CD3𝞯 signaling domain. The declaration asserts that CER-T cells were co- cultured at a 1:1 effector: target ratio with A2780 ovarian cancer cells in the presence of 0.5 pM niraparib, 1.56 pM olaparib, or no drug. CER constructs containing TLR2 signaling domain (Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3𝞯 signaling domain- TLR2 signaling domain or Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-TLR2 signaling domain-CD3𝞯 signaling domain) exhibited superior cytotoxicity compared to the CER construct lacking TLR2 in combination with either PARP inhibitor. The Applicant asserts that, furthermore, co-culture of CER-T cells containing Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-CD3𝞯 signaling domain- TLR2 signaling domain construct or Tim4 binding domain-CD28 transmembrane domain-CD28 signaling domain-TLR2 signaling domain-CD3𝞯 signaling domain construct with A2780 cells and a PARP inhibitor resulted in enhanced secretion of IFNy and TNFa compared to the CER lacking TLR2.
The Applicant also argues that in a second post-filing date study, T cells engineered to express a representative chimeric engulfment receptor according to the present claims (Tim4 binding domain, CD28 transmembrane domain, CD28 signaling domain, TLR2 signaling domain, and CD3𝞯 signaling domain) were co- cultured with A2780 ovarian cancer cells and subtherapeutic doses of a representative PARP inhibitor niraparib (0.5 pM) or olaparib (1.5 pM). The Applicant asserts that the combination demonstrated synergistic cytotoxicity far exceeding CER monotherapy or PARP inhibitor, specifically, niraparib alone eliminated 23% of A2780 cells; CER (Tim4-CD28-TLR2-CD3𝞯) alone eliminated 39%; but their combination eliminated 58%. The Applicant asserts that CER (Tim4-CD28-CD3𝞯-TLR2) alone eliminated 19% of cells, yet the niraparib + CER (Tim4-CD28-CD3𝞯-TLR2) combination eliminated 81%. The Applicant also asserts that Olaparib combinations were similarly synergistic: olaparib + CER (Tim4-CD28-TLR2-CD3𝞯) eliminated 66%, and olaparib + CER (Tim4-CD28-CD3𝞯-TLR2) eliminated 73%, compared to 34% for olaparib alone.
The Applicant argues that these results establish that the claimed combination of a CER comprising a wildtype Tim4 binding domain, a CD28 signaling domain, a CD3𝞯 signaling domain, and a TLR2 signaling domain with a PARP inhibitor as recited in the claims produces synergistic cytotoxicity and enhanced inflammatory cytokine production against ovarian cancer cells. The Applicant argues that in view of these remarks, the pending claims are nonobvious over Corey, Heo, and Lai.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s arguments that (i) none of the cited references teach or suggest that incorporation of any combination of CD28, CD3𝞯, and TLR2 signaling domains would confer engulfment phenotype in a CER construct and (ii) nothing in Lai teaches or suggests incorporating these signaling domains into a CER comprising a wildtype Tim4 binding domain; note that CERs have a similar design to CARs, in that they both comprise an extracellular target binding domain and intracellular signaling components; and that the activation, expansion, and survival of CAR T cells can be enhanced by incorporating CD3ζ, CD28, and TLR2 intracellular signaling domains into the CAR. Given these teachings, it would have been obvious to a skilled artisan, with the goal of enhancing the activation, expansion, and survival of Sun et al.’s Tim4-based CER T-cells, to incorporate the CD3ζ, CD28, and TLR2 intracellular signaling domains into the intracellular domain of the CER with a reasonable expectation of success.
Not only would an artisan reasonably expect that the addition of these intracellular signaling domains into the CER would improve expansion and survival of the Tim4-based CER T-cells, but an artisan would also reasonably expect that the inherent phagocytic capacity of the Tim4-based CER T-cells to be enhanced by the addition of these signaling domains given that they enhance the inherent cytotoxic capacity of CAR T cells. Furthermore, by incorporating these signaling domains into the Tim4-based CER T-cells, the phagocytic capacity of the Tim4-based CER T-cells would be complemented by an additional cytotoxic capacity that is afforded by the CD3ζ, CD28, and TLR2 intracellular signaling domains. Moreover, complementing the phagocytic capacity of the Tim4-based CER T-cells with a cytotoxic capability could be further enhanced by specifically selecting CD8+ in which the CER can be expressed. It is well-known that CD8+ T cells, also known as cytotoxic T lymphocytes (CTLs), play a crucial role in the immune response by targeting and killing infected or malignant cells.
Regarding the Applicant’s argument that the rejection is improper in view of objective evidence of unexpected results, namely, that the experimental data in the specification and post-filing date studies provide compelling evidence that use of the claimed combination led to unexpectedly enhanced and synergistic anti-tumor cell activity and cytokine production that were not taught or suggested by the cited references; note that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). See MPEP 2143.02.I.
Therefore, while the Examiner agrees that the Applicant has demonstrated that the claimed therapeutic combination has enhanced and synergistic anti-tumor cell activity and cytokine production when compared to monotherapy with either agent, the Examiner still maintains that it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Sun et al. to incorporate the teachings of Heo and Duggan and Lai et al. to include that Sun et al.’s CER01+ T cells are used to treat ovarian cancer in combination with a PARP inhibitor. The Examiner maintains that in view of the combined reference teachings, a skilled artisan would reasonably expect that claimed combination would lead to expectedly enhanced and synergistic anti-tumor cell activity.
There is an ongoing need for new compositions and methods of treating various cancers by enhancing the removal of apoptotic, damaged, or necrotic cells from the body that have been affected by cytotoxic treatments (Sun et al.). Phagocytosis of damaged, apoptotic cells is typically a non-inflammatory process; however inflammation can be beneficial for clearing apoptotic tumor cells because it induces an immune response to residual tumor cells (Sun et al.). Tim4-based CER T-cells, which direct phagocytic removal of apoptotic cells in a PS-dependent manner, have been designed to generate this targeted inflammatory response (Sun et al.). PS is known as a pro-engulfment marker or “eat me” signal that is expressed on the surface of apoptotic cells (Sun et al.). Tim4-based CER T-cells display a synergistic anti-tumor effect with anti-cancer therapies (Sun et al.).
Given the known applications and synergistic effect of Tim4-based CER T-cells in combination with anti-cancer therapies; the applications of niraparib, a PARP (or DNA repair) inhibitor, for the treatment of ovarian cancer by apoptosis; and Sun et al.’s suggestion that their CER modified cells can be administered in combination with chemotherapies, including DNA repair inhibitors, to clear cells displaying pro-apoptotic markers as a result of chemotherapy; it would have been obvious to a skilled artisan, with the goal of improving the treatment of ovarian cancer with niraparib, which induces apoptosis, to apply Sun et al.’s Tim4-based CER T-cells in Heo and Duggan’s niraparib-based treatment method with a reasonable expectation of success.
A skilled artisan would have reasonably expected that the Tim4-based CER T-cells would have a synergistic effect with niraparib for treating ovarian cancer by clearing cells displaying pro-apoptotic markers, such as PS, as a result of niraparib therapy, especially in the absence of evidence to the contrary. In view of the teachings in the art, a skilled artisan would reasonably expect that these two therapies would have positive feedback affect one another. The PARPi causes apoptosis which increases the amount of expressed PS for the Tim4-based CER T-cells to recognize and mediate the removal of the apoptotic cells by the Tim4-based CER T-cells. Then this removal of the apoptotic cells by the Tim4-based CER T-cells would allow for further penetration by the PARPi into the tumour microenvironment thereby leading to more apoptosis are more PS-dependent apoptotic cell clearance.
As such, the applicant’s arguments have not been found persuasive.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 8, 20, 32, 36-37, 50, 76, and 86-88 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of U.S. Patent No. 12,303,551 (the ‘551 Patent, a reference of record) in view of Sun et al. 2017 (WO2018064076, an IDS reference filed 06/12/2025), Heo and Duggan 2018 (Targeted Oncol. 13:533–539, a reference of record), and Lai et al. 2018 (Leukemia 32, 801–808, a reference of record) for the reasons of record.
The Applicant’s arguments have been fully considered but have not been found persuasive for the reasons outlined in the Examiner’s response to the Applicant’s arguments under 35 U.S.C. 103.
Claims 1, 3, 8, 20, 32, 36-37, 50, 76, and 86-88 stand (provisionally) rejected on the ground of nonstatutory double patenting as being unpatentable over the claims in the following U.S. Patents and co-pending Applications in view of Sun et al. 2017 (WO2018064076, an IDS reference filed 06/12/2025), Heo and Duggan 2018 (Targeted Oncol. 13:533–539, a reference of record), and Lai et al. 2018 (Leukemia 32, 801–808, a reference of record) for the reasons of record and similar reasons as the rejection over the claims in ‘551 Patent outlined above.
Claims 1-11 of U.S. Patent No. 12,291,557 (a reference of record).
Claims 1-27 of U.S. Patent No. 11,708,423 (a reference of record).
Claims 1, 2, 4-6, 8, 11-13, 15, 17-20, 22-31, 46-49, and 63 of co-pending U.S. Application No. 18/292,782.
Claims 2, 8, 10, 13-18, 20, 21, 23, 25, 32, 35, 36, 38, 39, 40, 42-46, and 48 of co-pending U.S. Application No. 19/092,996.
Claims 1, 3-6, 10, 11, 14-19, 23, 27, 29-31, 35, 37, and 69 of co-pending U.S. Application No. 19/263,356.
The nonstatutory double patenting rejections to the co-pending Applications 18/292,782, 19/092,996, and 19/263,356 are provisional because the patentably indistinct claims have not in fact been patented.
The Applicant’s arguments have been fully considered but have not been found persuasive for the reasons outlined in the Examiner’s response to the Applicant’s arguments under 35 U.S.C. 103.
Furthermore, regarding the Applicant’s argument that the present application is the earlier-filed application with respect to the '782 application and therefore there is no possible unjustified timewise extension of patent rights; note that it is proper for an examiner to make a provisional double patenting rejection between co-pending Applications regardless if the instant Application has an earlier filing date. See MPEP 804I.B.
An examiner may become aware of two or more copending applications which share the same inventive entity, at least one common (joint) inventor, a common applicant, and/or a common owner/assignee, or that claim an invention resulting from activities undertaken within the scope of a joint research agreement as defined in 35 U.S.C. 102(c) or pre-AIA 35 U.S.C. 103(c)(2) and (3), that would raise an issue of double patenting if one of the applications became a patent. Where this issue can be addressed without violating the confidential status of applications (35 U.S.C. 122 ), the courts have sanctioned the practice of making applicant aware of the potential double patenting problem if one of the applications became a patent by permitting the examiner to make a provisional rejection on the ground of double patenting. A provisional double patenting rejection should be made and maintained by the examiner until the rejection has been obviated or is no longer applicable except as noted below. MPEP 804I.B.
If a provisional nonstatutory double patenting rejection is the only rejection remaining in an application having the earlier patent term filing date, the examiner should withdraw the rejection in the application having the earlier patent term filing date and permit that application to issue as a patent, thereby converting the provisional nonstatutory double patenting rejection in the other application into a nonstatutory double patenting rejection upon issuance of the patent. MPEP 804I.B.1(b)(i)
In the instant case, the provisional nonstatutory double patenting rejections over claims 1, 2, 4-6, 8, 11-13, 15, 17-20, 22-31, 46-49, and 63 of co-pending U.S. Application No. 18/292,782 will not be withdrawn at this time in view of the remaining non-double patenting rejections outlined above. While the Examiner agrees that that instant Application has an early effective filing date than Application No. 18/292,782; the provisional nonstatutory double patenting rejections over the claims in these later-filed co-pending applications are still proper.
Allowable Subject Matter
A chimeric engulfment receptor comprising the amino acid sequence set forth in SEQ ID NOs: 71, 228, 229, 239, or 240 is free of the prior art.
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 Grace H. Lunde whose telephone number is (703)756-1851. The examiner can normally be reached Monday - Thursday 6:00 a.m. - 3:00 p.m. (EST).
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, Misook Yu can be reached on (571) 272-0839. 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.
/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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