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 without traverse of group I, claims 1, 3, 5, 9-14, 17-18, in the reply filed on 5/21/26 is acknowledged. Applicant has further elected HLA-A as the species of first and second epitope, CD8a as the species of hinge and transmembrane domain, and PD-1 as the species of intracellular domain. Upon reconsideration, an iCAR with PD-1 hinge/transmembrane domain is also being included in the examination Claims 19-21, 24-27, and 29-30 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 1, 3, 5 9-14, 17-18 read on the elected invention and 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 1, 3, 5 9-14, and 17-18 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.
The scope of claim 1 which recites that the cells are “inactivated” cannot be established. The specification does not specifically define the term. It is unclear if the claim would encompass inhibition of immune cell activation, or immune cells that are not activated upon iCAR triggering, or whether the claims would require that the cell itself is killed or otherwise actively destroyed. The specification on page 14 discloses that inhibitory CAR (iCAR) refers to engineered immune receptors capable of inhibiting the activation of an immune cell. For example, the specification disclose (and dependent claims recite) that the iCAR can have a PD-1 signaling domain. This is known in the art to induce an inhibitory signal that can reduce immune cell activation or that cause T cells to not become activated. For example, see WO2019/068007 below. For the purposes of examination, the claims are being interpreted as encompassing iCAR that inhibit T cell activation or an iCAR that causes immune cells to not be activated.
The scope of claim 17 is unclear. Claim 17 recites that immune cell further comprises a synNotch receptor, wherein the synNotch receptors activates the CAR and the iCAR expression when the immune cell is in a tumor microenvironment. This is depicted in Fig. 17 of the instant specification, wherein an immune cell expresses a synNotch receptor, and activation of the synNotch releases a transcription factor that induces expression of an CAR and iCAR from a nucleic acid within the immune effector cell. In other words, in the synNotch system, the iCAR and CAR are not expressed until the synNotch is activated in a tumor microenvironment. However, claim 17 depends from claim 1, which is directed to an immune cell comprising a CAR and an iCAR, i.e. the CAR must already be expressed and present. Claim 17 does not limit the immune effector cells to those that are present in a tumor microenvironment, but rather recites that the iCAR and CAR are expressed “when the immune cell is in a tumor microenvironment”. Therefore, it appears that claim 17 would encompass an immune cell as depicted in Fig 17F (which only comprises a nucleic acid encoding CARs, and not CAR proteins). Or would claim 17 actually require that the immune cell are present in the tumor microenvironment and already expressing the CAR and iCAR such that the limitations of claim 1 are met (i.e. that the cell comprises the iCAR and CAR)? The scope of the claim is unclear and indefinite.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 17 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 17 appears to encompass a cell in which the CAR and iCAR are not yet expressed (i.e. the cell does not yet comprise the iCAR and CAR), but wherein they are capable of being induced from a nucleic acid upon activation of a synNotch receptor (see Fig 17F of the instant specification).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1, 3, 5 9-14, 17-18 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 immune cells comprising a CAR and iCAR that bind to a first and second epitope.
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 claimed genus. See MPEP 2163.
The instant claims are directed to a genus of immune cells comprising a genus of CAR and iCAR binding to a genus of first and second epitopes. The claims encompass CAR and iCAR having a huge genus of structurally and functionally distinct antigen binding regions that function to bind to any first and second epitope. The claims also require that the immune cells comprising said CAR function to be activated upon binding to the first epitope and not the second epitope, and that the immune cells are inactivated when the immune cell binds to the first and second epitopes. For example, the claims would encompass numerous functionally distinct signaling domains and antigen binding regions. Claim 3 recites that the first and second epitope are from a first and second allele from an HLA gene. This also encompass a genus of CAR antigen binding domains, since HLA represents an extremely large genus of polymorphic alleles of different HLA class I, class II, HLA III, and minor HLA antigens. Likewise, claim 5 encompass CAR that bind an epitope from any polymorphic allele that is lost in a cancer cell, which also encompasses an extremely large genus of alleles that include HLA as well as a genus of structurally distinct tumor suppressor genes, for example.
Furthermore, the claims encompass antibody antigen binding regions that function in a CAR to bind said first and second epitope. The state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. See, for example, Rabia, 2018, which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity (see page 4). The instant specification does not disclose a correlation between structure and claimed function, nor does it disclose a representative number of species. The specification discloses a CAR/iCAR comprising an amino acid sequence of an antibody binding domain having VH/VL of an HLA-A2:01 antibody BB7.2, and CAR comprising an amino acid sequence of antigen binding domain specific toHLA-A2:01 antibody clone 13, wherein iCAR comprise signaling domains of PD-1 or CTLA-4. This is not representative of the enormous genus of immune effector cells having a CAR/iCAR as broadly encompassed in the present claims.
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)).
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.
Given the claimed broadly class of CAR, 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 CAR 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 CAR 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.
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) 1, 3, 5, 10-14, 18 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2019/068007.
WO2019/068007 teaches an immune cell comprising an aCAR that binds a first epitope and an iCAR that binds to a second epitope, wherein the immune cell is activated when the immune cells binds to the first epitope and does not bind to the second epitope, and wherein the immune cell is not activated or wherein activation is inhibited (i.e. “inactivated”) when the immune cell binds to the first and second epitopes (See Fig. 1-2 and pages 17-21, 27, and 33 in particular). WO2019/068007 teaches pharmaceutical compositions comprising said immune effector cells. WO2019/068007 teaches that the iCAR contains signaling elements from PD-1 (See examples, in particular). WO2019/068007 teaches that the aCAR can have a CD8 or CD28 hinge and a CD28 and CD3 intracellular domain and that the iCAR can comprise a PD-1 hinge/transmembrane domain (See Example 5, in particular). Regarding claim 5, WO2019/068007 teaches an embodiment wherein the extracellular domain of the iCAR binds to an HLA that is lost in the cancer cell (i.e. a polymorphic allele), and the extracellular domain of the aCAR binds to a tumor associated antigen (See paragraph 268, examples, Table 1, in particular). Regarding claim 3, WO2019/068007 teaches another embodiment where both the aCAR and the iCAR recognize different allelic variants of the same target gene for which the patient is heterozygous due to LOH in tumor cells, wherein the aCAR targets an allelic variant that is expressed by the tumor cells and not affected by LOH, while the iCAR targets the product of the same gene that has been lost from the tumor cells to LOH, and wherein both of said alleles are present in normal tissue (see page 31-32, in particular). WO 2019/068007 also teaches examples of allelic variants including HLA-A alleles, and that the iCAR can be specific for HLA allele and that the a-CAR can be specific for an HLA-A allele (i.e. from an HLA gene, see page 58-59, in particular). Thus, the ordinary artisan would once envisage that the embodiment described by WO2019/068007 involving using different allelic variants of the same gene would include an HLA allelic variant.
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.
Claims 1, 3, 5, 9-14, 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/068007, in view of US 2016/0355590
The teachings of WO2019/068007 are described above. It is noted that even though the teaching of the reference anticipate claim 3 for the reasons set forth above, it would also be obvious to select an HLA gene, such as HLA-A, as the allelic variant of the same gene that the iCAR and aCAR are specific for.
The reference differs from the claimed invention in that it does not explicitly teach a CD8 hinge and transmembrane domain..
The ‘590 publication teaches that CD8a can be used as a hinge and transmembrane domain in CAR (see paragraph 6, in particular). The ‘590 publication also teaches CARs for treating cancer can bind to HLA-DR (see paragraph 85, 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 use a CAR targeting HLA-DR and having a CD8 hinge and transmembrane domain, as the aCAR for use with the HLA-A LOH iCAR in the immune effector cells of WO2019/068007. The ordinary artisan would be motivated to do so with a reasonable expectation of success since the ‘590 publication teaches that targeting HLA-DR is useful for treating B cell lymphoma. A combination of an aCAR targeting HLA-DR and an iCAR targeting an HLA that is lost in cancer cells due to LOH, would also be within the scope of the instant claim 3 or 5. Furthermore, it would be obvious to use CD8hing/transmembrane in a CAR construct and 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).
Claims 1, 3, 5, 10-14, and 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO2019/068007, in view of 20170233474
The teachings of WO2019/068007 are described above. It is noted that even though the teaching of the reference anticipated claim 3 for the reasons set forth above, it would also be obvious to select an HLA as the allelic variant of the same gene that the iCAR and aCAR are specific for.
The reference differs from the claimed invention in that it does not explicitly teach that the immune effector cell comprises a SynNotch receptor.
The ‘474 publication teaches a synNotch system that acts as a transcriptional switch to induce CAR expression when an immune cell expressing the synNotch receptor binds to a tumor antigen (i.e. in the tumor microenvironment, see entire document and paragraphs 449- 451, and the drawings in particular). The ‘474 publication teaches that doing so is a safety mechanism.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a synNotch receptor, as taught by the ‘474 publication, to induce expression of the CARs of WO 2019/068007. The ordinary artisan would be motivated to do so with a reasonable expectation of success because the ‘474 publication teaches that is a safety mechanisms that allows expression of the CAR in the tumor microenvironment after binding to a tumor antigen.
No claim is allowed. Claims 12-13 are free of the art.
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 from 7am to 3pm.
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.
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Amy E. Juedes
Patent Examiner
Technology Center 1600
/AMY E JUEDES/Primary Examiner, Art Unit 1644
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