DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The preliminary amendment filed on 02/20/2024 cancelled claims 1-58 and added new claims 59-78. There are no claims withdrawn and no claims amended. Claims 59-78 are pending and will be examined on the merits.
Priority
Provisional application 63/122,839 is acknowledged as disclosing the claimed invention and the effective filing date is 12/08/2020.
Information Disclosure Statement
The Information Disclosure Statements filed on 06/05/2023, 03/24/2025, and 11/20/2025 have been considered. Signed copies are enclosed.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 59 and 61-78 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 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. This is a written description rejection.
Claim 59 recites “a polynucleotide comprising a human codon-optimized sequence encoding an anti-epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR), wherein the CAR comprises: (a) an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1; (b) a polypeptide spacer; (c) a transmembrane domain; and (d) an intracellular signaling domain.” Claims 61-63 further limit the spacer and domains of this polynucleotide. Claim 64 further limits additional elements of the polynucleotide, and claim 65 recites that the polynucleotide comprises a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 10. Claim 66 recites a vector comprising the polynucleotide of claim 59, and claim 67 recites an isolated cell comprising the polynucleotide of claim 59. Claims 68-72 further limit the isolated cell of claim 67, and claim 73 discloses a pharmaceutical composition comprising the isolated cell of claim 67. Claims 74-78 recite a method of inhibiting, ameliorating or treating a cancer in a subject comprising administering the cell of claim 67 to the subject. Therefore, claims 59 and 61-78 are all drawn to a polynucleotide comprising an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1.
The specification defines, in paragraph [0083], scFv as “single chain antibodies (scFv)”, and defines the term "antibody," as an immunoglobulin molecule which is able to specifically bind to a specific epitope on an antigen. Interpreted in light of the specification’s definition, the scFv polypeptide of instant claim 59 is claimed based on its function; i.e. the ability to specifically bind to a specific epitope on an antigen; in this case, the antigen is EFGR. The specification recites the polynucleotide sequence of a single scFv polypeptide capable of specifically binding to an EGFR806 epitope in SEQ ID NO: 01. The specification does not recite any other scFv sequences capable of binding to EFGR806 or any other epitope of EGFR, nor does it disclose the regions of the nucleotide sequence of SEQ ID NO: 1 that are important for binding EGFR806. In Example 1, the specification discloses that three novel sequences of EGFR806CAR constructs were tested. According to Figure 1, each of these constructs contained the scFv polypeptide disclosed in SEQ ID NO: 01, also referred to as EGFR806CAR. The specification does not recite a definition for “% sequence identity” or otherwise impose any limitations on the variation in sequence identity that may be made to SEQ ID NO: 1.
Claims 59 and 61-78 are drawn to “a polynucleotide comprising an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1.” The antibody, or scFv fragment, encoded by SEQ ID NO: 1 and claimed in instant claim 60, meets the written description requirement of 35 USC 112(a). However, a nucleotide sequence having at least 95% identity to SEQ ID NO: 1 does not meet the written description requirement of 35 USC 112(a), as the specification is silent as to what regions are required for a given antibody to bind to EGFR806CAR and where the 5% variation in sequence identity may occur to retain binding functionality. Therefore, the specification does not encompass the recited breadth of the claims.
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.)
Claims 59 and 61-78 speak to “a polynucleotide comprising an scFv capable of specifically binding EGFR…”. As such, the claims are directed to an antibody defined by function (binding EGFR). Additionally, the claims speak to the broad genus of “a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1”, and the specification provides evidence for one species within this genus – the nucleotide sequence of SEQ ID NO: 1.
To fulfill the written description requirements set forth under 35 U.S.C. 112(a), the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicant has possession of the claimed invention. To adequately describe the genus of antibodies, Applicant must adequately describe which combination of variable regions and framework regions that give rise to an antibody with the claimed immunological function. The instant specification, however, does not disclose distinguishing and identifying features of a representative number of members of the genus of antibodies to which the claims are drawn, such as a correlation between the structure of the antibody and its recited function (binding EGFR), so that the skilled artisan could immediately envision, or recognize, at least a substantial number of members of the claimed genus of antibodies. The specification fails to disclose what combination of variable regions and framework regions (other than those of SEQ ID NO: 1) are essential for antibody binding, or which amino acids might be added, replaced or deleted so that the resultant antibody retains the binding specificity of its parent, or by which other amino acids the essential amino acids might be replaced so that the resultant antibody retains the binding specificity of its parent. Therefore, the specification fails to adequately describe at least a substantial number of members of the genus of antibodies to which the claims refer; and accordingly, the specification fails to adequately describe at least a substantial number of members of the claimed genus of antibodies.
MPEP §2163 states:
“An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. For example, the amino acid sequence of a protein along with knowledge of the genetic code might put an inventor in possession of the genus of nucleic acids capable of encoding the protein, but the same information would not place the inventor in possession of the naturally-occurring DNA or mRNA encoding the protein. See In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993); In re Deuel, 51 F.3d 1552, 34 USPQ2d 1210 (Fed. Cir. 1995).”
The MPEP §2163 additionally states:
“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 (see i)(A) above), reduction to drawings (see i)(B) above), 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 inventor was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ( "[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]. "See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) "[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).”
“For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).”
As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence that a variant of a given polypeptide would necessarily bind to a given antibody. Moreover, as evidenced by Greenspan et al. (Nature Biotechnology 7: 936-937, 1999), defining epitopes is not as easy as it seems. Greenspan et al. recommends defining an epitope by the structural characterization of the molecular interface between the antigen and the antibody is necessary to define an "epitope" (page 937, column 2). According to Greenspan et al., an epitope will include residues that make contacts with a ligand, here the antibody, but are energetically neutral, or even destabilizing to binding. Furthermore, an epitope will not include any residue not contacted by the antibody, even though substitution of such a residue might profoundly affect binding. Accordingly, it follows that the immunoepitopes that can elicit antibodies that bind to a given antigen can only be identified empirically. Therefore, absent a detailed and particular description of a representative number, or at least a substantial number of the members of the genus of immunoepitopes, the skilled artisan could not immediately recognize or distinguish members of the claimed genus of antibodies.
It is well settled that the exchanging of CDRs among between antibodies is not predictable. While the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen- binding domains and surrounding framework regions of antibodies. For example, Giusti et al. (Proc. Natl. Acad. Sci. USA. 1987 May; 84 (9): 2926-2930) teaches the specificity and affinity of an antibody is exquisitely sensitive to amino acid substitutions within the primary structure of the antibody, since only a single amino acid substitution in the heavy chain of an antibody completely altered the binding specificity of an antibody that binds phosphocholine, such that the altered antibody fails to bind phosphocholine but instead binds DNA (see entire document [e.g., the abstract]). This unpredictability of single amino acid changes in an antibody is underscored by Winkler et al (J Immunol. 2000 Oct 15; 165 (8): 4505-14.) who teach that single amino acid changes in antibody side chains can result in unpredictable and substantial changes in antibody specificity; (see entire document [e.g., the abstract]). Chien et al. (Proc. Natl. Acad. Sci. USA. 1989 Jul; 86 (14): 5532-5536) teaches that significant structural and functional changes in an antigen-binding site can be caused by amino acid substitutions in the primary structure of an antibody, including substitutions at a site remote from the complementarity determining regions of the antigen- binding domain; (see entire document [e.g., the abstract]). Similarly, but more recently, Caldas et al. (Mol. Immunol. 2003 May; 39 (15): 941-952) teaches an unexpected effect of substituting a framework residue upon binding specificity during the humanization of an antibody that binds CD18 (see entire document [e.g., the abstract]). Casadevall et al. (PNAS, Vol 109 No. 31, pages 12272-12273) underscores the importance of the framework regions with regard to antibody affinity and binding specificity.
Sela-Culang et al. (Frontiers in Immunology, 2013 Vol. 4, article 302, pages 1-13) clearly set forth the role of CDRs, framework regions, and constant regions in antibody specificity and affinity. Sela-Culang et al. disclose that the belief CDRs of an antibody are responsible for antigen recognition while the constant domains mediate effector activation is an oversimplification, and that some residues within the CDRs never participate in antigen binding while some off-CDR residues are critical for antigen interaction. Sela-Culang et al. further disclose that only 20-33% of the residues within the CDRs actually participate in antigen binding (see page 4) and that it is well established that some of the framework (FR) residues play an important role in antigen binding (see page 7). This point is demonstrated by the fact that humanizing an antibody by grafting only the CDRs usually results in a significant drop or complete loss of antigen binding. Sela-Culang et al. also discloses that the framework region residues that affect binding can be divided into two categories: those that contact the antigen (which can be close in sequence to the CDRs or far from the CDRs in sequence but are in close proximity to it in 3-D structure) and those that are not in contact with the antigen but affect antigen binding indirectly (which can be in spatial proximity to the CDRs or not). The framework regions residues that are more distant from the paratope (i.e. binding residues) not only play a role in maintaining the overall structure of the variable (Fv) domains but may affect antigen binding itself by directing the relative orientation of the VH with relation to the VL and thus the orientation of the CDRs relative to each other (see page 7). Specific knowledge of the FR residues involved in antigen binding is critical for antibody design in general and for the humanization of antibodies in particular. Finally, Sela-Culang et al. disclose that the constant regions of antibodies play a role in antigen binding due to an allosteric influence of the constant domains on the structure of the variable domains as evidenced by the differences in affinity and specificities of antibodies with the same variable region but different isotypes (see page 8).
Consequently, because the art is unpredictable, in accordance with the MPEP, only the scFv encoded by the nucleotide sequence set forth in SEQ ID NO: 1, but not the full breadth of claims regarding any nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1, meets the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Applicant is reminded that Vas- Cath makes clear that the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 59, 61-62, 64, 66-70, and 73-78 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by WO 2020/210768, O'Rourke, 2020. The reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and (a)(2).
O’ Rourke recites an isolated nucleic acid molecule encoding a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of binding multiple isoforms of epidermal growth factor receptor (EGFR), a transmembrane domain, and an intracellular domain (page 3, lines 8-11). The antigen binding domain is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO: 1, which is a sequence of a scFv with 95% nucleotide sequence identity to instant SEQ ID NO: 1. Thus, O’Rouke recites a polynucleotide that anticipates instant claim 59. The polynucleotide of O’Rouke further comprises an IgG4 hinge (page 44, line 9), a CD28 transmembrane domain (page 43, line 22), and 4-1BB and CD3-zeta domains as signaling domains (page 47, lines 23-25). Thus, the polynucleotide of O’Rouke anticipates the polynucleotide of instant claim 61. Page 45 line 19 discloses a human IgG4 hinge spacer region of 12 amino acids, meeting the limitations of claim 62. Furthermore, O’Rourke discloses a promoter of transcription upstream of the nucleic acid sequence on page 66, meeting the limitation of instant claim 64.
O’Rourke discloses a vector that contains the polynucleotide described above on page 3, lines 12-13, anticipating claim 66. Also disclosed on page 3, lines 14-17, is a cell comprising the CAR of said polynucleotide, anticipating claim 67. Page 57 lines 15-18 disclose a T cell, meeting the limitations of instant claims 68-70. Lines 20-24 of page 57 disclose a composition comprising the modified T cells and a pharmaceutically acceptable carrier, anticipating instant claim 73. A method of treating cancer comprising administering this composition is described on page 57 as well, in lines 25+, anticipating claim 74. Page 58, line 8 discloses that the cells are specific to the subject, or autologous, anticipating claim 75. Page 58, line 12 discloses the cancer to be treated as glioblastoma, a solid tumor, meeting the limitations of instant claims 76-78. Further cancers to be treated with this method are recited on page 59 and 60, disclosing solid tumors and lymphomas, as well as “breast cancer, neck cancer, prostate cancer, ovarian cancer, cervical cancer, skin cancer, pancreatic cancer, colorectal cancer, renal cancer, liver cancer, brain cancer, lymphoma, leukemia, lung cancer, thyroid cancer, and the like”, further anticipating the claims of 76 and 77.
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 59-64 and 66-77 are rejected under 35 U.S.C. 103 as being unpatentable over WO/2017/027291, Jensen, 2017 in view of Mauro et al., Trends in Molecular Medicine, 2014, Vol. 20, No. 11 (hereinafter Mauro).
Claim 59 is drawn to a polynucleotide comprising a human codon-optimized sequence encoding an anti-epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR), wherein the CAR comprises (a) an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1; (b) a polypeptide spacer; (c) a transmembrane domain; and (d) an intracellular signaling domain. Jensen discloses, in one embodiment named in paragraph [0012], a nucleic acid encoding a CAR comprising a leader sequence, an inducible promotor, an scFv specific for EGFR806, an IgG4 hinge spacer, a CD-28 transmembrane domain, a signaling domain comprising a 4-1BB domain and a CD3-zeta domain, a linker with a P2A or T2A sequence, and a marker domain comprising EGFRt. In name, this molecule meets the limitations of claims 59-64. As claims 59-64 are drawn to sequences, however, the nucleic acid sequence for the EGFR806 scFv is 79% similar to the nucleotide sequence of SEQ ID NO:1. However, the amino acid sequences of the EGFR scFv is 100% to a translated version of SEQ ID NO:1. As the amino acid code is well known within the art (see Mauro), these two nucleotide sequences are obvious variants of each other. Additionally, the concept of codon optimization is well established, and the benefits are understood (see Mauro). Therefore, it would be obvious for one skilled in the art of genetic engineering to perform codon optimization on the scFv protein sequence of Jensen and arrive at the claimed sequence of instant claim 59. The same logic is applied to the IgG4 hinge spacer (72.2% nucleotide sequence identity and 100% amino acid sequence identity), the transmembrane domain (89.2% nucleotide sequence identity and 100% amino acid sequence identity) and the signaling domain (87.7% nucleotide identity and 100% amino acid sequence identity). As such, these obvious variants meet the limitations of claims 59-63.
Additionally, the recited nucleic acid of Jensen meets the limitations of claim 64, comprising all elements of claim 59 and three recited additional elements – a promotor, a T2A self-cleaving domain, and a EGFRt selectable marker.
The same polynucleotide is recited by Jensen in paragraph [0223]. In paragraph [0227], Jensen discloses a vector for expression of said polynucleotide, meeting the limitations of instant claim 66. Paragraph [0232] recites a cell comprising this polynucleotide, meeting the limitations of claim 67. The same paragraph further names the cell as a CD8+ T cytotoxic lymphocyte cell or a CD4+ T helper lymphocyte cell, meeting the limitations of claims 68-70. Furthermore, this paragraph recites the cell containing a second CAR with an scFv specific for a ligand on a B cell, and presents a list of ligands identical to that of claim 72, thereby meeting the limitations of claims 71 and 72.
Paragraph [0157] of Jensen recites a composition comprising the above cell, and paragraph [0161] additionally recites a vehicle, or excipient in said composition, meeting the limitations of instant claim 73. Paragraph [0175] recites a method of treating, ameliorating, or inhibiting a disease, comprising administering the above cell, and defines the disease as a cancer in paragraph [0117-0119], meeting the limitations of instant claim 74, 76, and 77. Paragraph [0174] states the cells that are administered are autologous, meeting the limitations of instant claim 75.
Therefore, Jensen names an obvious variant of the polynucleotide of claim 59 that meets the limitations of instant claims 59-64, a vector encoding said polynucleotide meeting the limitations of instant claim 66, a cell encoding said polynucleotide meeting the limitations of instant claims 67-72, a pharmaceutical composition meeting the limitations of instant claim 73, and a method of treating, ameliorating, or inhibiting a cancer that meets the limitations of instant claims 74-77.
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 59-64 and 67-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,458,167 in view of Mauro.
Claim 59 is drawn to a polynucleotide comprising a human codon-optimized sequence encoding an anti-epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR), wherein the CAR comprises (a) an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1; (b) a polypeptide spacer; (c) a transmembrane domain; and (d) an intracellular signaling domain. ‘167 discloses, in claim 1, a T cell comprising a CAR encoded by a polynucleotide, wherein the CAR comprises a 4-1BB signaling domain, a CD3-zeta signaling domain, a transmembrane domain, and an extracellular spacer comprising an IgG hinge spacer, and a ligand binding domain which specifically binds to EGFR and comprises the amino acid sequence of SEQ ID NO:19. The amino acid encoded by SEQ ID NO: 1 in instant claim 59 has 100% identity to ‘167 SEQ ID NO:19. As the amino acid code is well known within the art (see Mauro), these two nucleotide sequences are obvious variants of each other. Additionally, the concept of codon optimization is well established, and the benefits are understood (see Mauro). Therefore, it would be obvious for one skilled in the art of genetic engineering to perform human codon optimization on the scFv protein sequence of ‘167 and arrive at the claimed sequence of instant claim 59. Furthermore, ‘167 claims 1, 6-8, and 10 disclose amino acid sequences for the remaining parts of the CAR. The same logic is applied to the IgG4 hinge spacer, the transmembrane domain, and the signaling domain. As such, these obvious variants meet the limitations of claims 59-63. Additionally, the recited nucleic acid of ‘167 claims 6-8 meet the limitations of claim 64, comprising all elements of claim 59 and a EGFRt selectable marker.
‘167 claims 1 and 10 recite a T cell comprising this CAR polynucleotide, meeting the limitations of claim 67-69. ‘167 claims 3, 13, and 14 name the T cell as a CD8+ T cytotoxic lymphocyte cell or a CD4+ T helper lymphocyte cell, meeting the limitations of claims 67-70. Furthermore, ‘167 claim 1 recites the cell contains another CAR with an scFv specific for a ligand on a B cell, and ‘167 claims 4, 5, 11, and 12 recite the B cell ligand as CD19 or CD20, thereby meeting the limitations of claims 71 and 72.
‘167 claim 9 recites a composition comprising the T cell of claim 1 and a pharmaceutically acceptable excipient, meeting the limitations of instant claim 73.
Therefore, ‘167 names an obvious variant of the polynucleotide of claim 59 that meets the limitations of instant claims 59-64, a cell encoding said polynucleotide meeting the limitations of instant claims 67-72, and a pharmaceutical composition meeting the limitations of instant claim 73.
Claims 59-64 and 66-73 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,458,167 in view of Mauro as applied to claims 59-64 and 67-73 and further in view of Zhang et al. Biomark Res 5, 22 (2017) (hereinafter Zhang) . The teachings of '167 in view of Mauro regarding claims 59-64 and 67-73 are recited above, under paragraph 15. ‘167 does not teach a vector comprising the CAR polynucleotide, as in instant claim 66. However, ‘167 does teach a cell containing the CAR polynucleotide (see paragraph 15).
Zhang teaches that a delivery mechanism is needed to introduce a polynucleotide comprising a CAR into a cell for expression of the CAR, and that this mechanism is typically a vector (see page 3, right column). As ‘167 present a polynucleotide comprising a CAR and a cell containing said polynucleotide, a delivery mechanism must have been used. The teaching of Zhang indicates that vectors are commonly used in the art as this mechanism. This teaching would lead one of ordinary skill in the art to believe a vector was used to deliver the polynucleotide of ‘167 into the cell of ‘167. Therefore, ‘167 in view of Zhang discloses a vector comprising the polynucleotide of the CAR, meeting the limitations of instant claim 66.
Claims 59-64 and 67-78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 11,458,167 in view of Mauro as applied to claims 59-64 and 67-73 and further in view of WO 2020/210768, O'Rourke, 2020. The teachings of '167 in view of Mauro regarding claims 59-64 and 67-73 are recited above, under paragraph 15. ‘167 does not teach a method of inhibiting, ameliorating or treating a cancer in a subject comprising administering the cell or pharmaceutical composition of ‘167 to the subject, as in instant claim 74. ‘167 does not teach the cell as autologous to the subject (as in instant claim 75), or the cancer as a solid tumor or lymphoma (as in instant claim 76), nor does it present the cancer as one from the list of instant claim 77 or glioblastoma, in instant claim 78.
O’Rourke teaches a method of treating cancer comprising administering a composition containing a T cell that comprises a CAR that meets the limitations of instant claim 59 (see paragraph 9 for the full teaching of O’Rourke) on pages 57-60. These same pages teach the cell is autologous to the subject, that the cancer may be a solid tumor, and that the solid tumor may be one from the list given in instant claim 77. Furthermore, O’Rourke teaches that the method may be used to treat glioblastoma, meeting the limitations of instant claim 78.
It would have been obvious to one skilled in the art before the effective filing date of the invention to use the CAR and a cell containing the CAR of ‘167 to treat cancer using the method of O’Rourke, as the CAR and the cell containing the CAR of O’Rourke have the same target as the CAR and the cell containing the CAR of ‘167 (EFGR). The CAR of ‘167 and the CAR of O’Rourke contain the same functional components and have a different EGFR targeting scFv. However, since both the scFv of ‘167 and O’Rourke target the same receptor, and the function of the CAR remains the same, the substitution of the CAR of ‘167 for the CAR of O’Rourke in the method of O’Rourke would have yielded predictable results; i.e., treating the cancer. Therefore, as MPEP 2143(I)(B) recites that simple substitution of one known element for another to obtain predictable results is obvious, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute the invention of ‘167 for the CAR or cell comprising the CAR of O’Rourke into the method of treating cancer presented in O’Rourke in order to treat glioblastoma, thus rendering the instant invention of claims 74-78 obvious.
Claims 59-64, 67-72, 74, and 76-77 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 10-16 of U.S. Patent No. 11,123,369 in view of Mauro.
Claim 59 is drawn to a polynucleotide comprising a human codon-optimized sequence encoding an anti-epidermal growth factor receptor (EGFR) chimeric antigen receptor (CAR), wherein the CAR comprises (a) an scFv capable of specifically binding EGFR, wherein the scFv is encoded by a nucleotide sequence having at least 95% sequence identity to SEQ ID NO: 1; (b) a polypeptide spacer; (c) a transmembrane domain; and (d) an intracellular signaling domain. ‘369 discloses, in claim 1, a method of treating, ameliorating, or inhibiting a non-B cell cancer in a human subject, wherein the cancer comprises an EGFR+ cell, the method comprising administering to the subject a human T cell comprising: a CAR capable of specifically binding to EGFR, wherein the second CAR comprises a second ligand binding domain encoded by a sequence having at least 95% identity with the nucleotide sequence of SEQ ID NO: 20, wherein the CAR comprises an IgG4 hinge spacer domain, a CD28 transmembrane domain, an intracellular signaling domain, and a cell surface selectable marker. ‘369 claim 4 recites the intracellular signaling domain as comprising a 4-1BB and a CD3-zeta domain. The nucleic acid sequence of ‘369 SEQ ID NO: 20 is 79% similar to the nucleotide sequence of instant SEQ ID NO:1. However, the amino acid sequences encoded by ‘369 SEQ ID NO:20 and SEQ ID NO:1 are identical. As the amino acid code is well known within the art (see Mauro), these two nucleotide sequences are obvious variants of each other. Additionally, the concept of codon optimization is well established, and the benefits are understood (see Mauro). Therefore, it would be obvious for one skilled in the art of genetic engineering to perform codon optimization on ‘369 SEQ ID NO: 20 and arrive at the claimed sequence of instant claim 59. Furthermore, ‘369 claim 3 recites “the method of claim 1, wherein the second ligand binding domain comprises the amino acid sequence of SEQ ID NO:19.” ‘369 SEQ ID NO:19 is identical to the amino acid sequence encoded by instant SEQ ID NO:1, and therefore instant claim 60 reads on ‘369 claim 3. As such, ‘369 claims 1-4 meet the limitations of claims 59-63.
‘369 claims 5-7 the cell surface selectable marker as an EGFRt polypeptide, meeting the limitations of claim 64.
‘369 claim 1 recites a human T cell comprising this CAR polynucleotide, meeting the limitations of claim 67-69. ‘369 claim 10 names the T cell as a CD8+ T cell or a CD4+ T cell, meeting the limitations of claims 67-70. Furthermore, ‘369 claim 1 recites the T cell contains another CAR with an scFv capable of specifically binding CD19, and thus meets the limitations of claims 71 and 72.
‘369 claim 1 recites a method of treating, ameliorating, or inhibiting a non-B cell cancer in a human subject, comprising administering the above cell, meeting the limitations of instant claim 74. ‘369 claim 14 recites the cancer comprises a solid tumor, meeting the limitations of instant claim 76, and ‘369 claim 15 recites a list of cancers that meets the limitations of instant claim 77.
Therefore, ‘369 names an obvious variant of the polynucleotide of claim 59 that meets the limitations of instant claims 59-64, a cell encoding said polynucleotide meeting the limitations of instant claims 67-72, and a method of treating, ameliorating, or inhibiting a cancer that meets the limitations of instant claims 74 and 76-77.
Claims 59-64, 66-72, and 74-77 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 10-16 of U.S. Patent No. 11,123,369 in view of Mauro as applied to claims 59-64, 67-72, 74, and 76-77 and further in view of Zhang. The teachings of '369 in view of Mauro regarding claims 59-64, 67-72, 74, and 76-77 are addressed above in paragraph 18. ‘369 does not explicitly disclose a vector comprising the CAR polynucleotide, as in instant claim 66. However, ‘369 does teach a cell containing the CAR polynucleotide (see paragraph 18).
Zhang teaches that a delivery mechanism is needed to introduce a polynucleotide comprising a CAR into a cell for expression of the CAR, and that this mechanism is typically a vector (see page 3, right column). As ‘369 presents a polynucleotide comprising a CAR and a cell containing said polynucleotide, a delivery mechanism must have been used. The teaching of Zhang indicates that vectors are commonly used in the art as this mechanism. This teaching would lead one of ordinary skill in the art to believe a vector was used to deliver the polynucleotide of ‘369 into the cell of ‘369. Therefore, ‘369 in view of Zhang discloses a vector comprising the polynucleotide of the CAR, meeting the limitations of instant claim 66.
Claims 59-64 and 67-78 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 and 10-16 of U.S. Patent No. 11,123,369 in view of Mauro as applied to claims 59-64, 67-72, 74, and 76-77 and further in view of WO 2020/210768, O'Rourke, 2020. The teachings of '369 in view of Mauro regarding claims 59-64, 67-72, 74, and 76-77 are addressed above in paragraph 18. ‘369 does not explicitly disclose a pharmaceutical composition comprising the cell comprising the CAR and a pharmaceutically acceptable excipient as in instant claim 73. ‘369 also does not teach that the cell used in the method of claim 1 is autologous to the subject as in instant claim 75. ‘369 does not name glioblastoma as a cancer to be treated by the method and thus does not meet the limitations of instant claim 78.
Lines 20-24 of page 57 of O’Rourke disclose a composition comprising the modified T cells and a pharmaceutically acceptable carrier, meeting the limitations of instant claim 73. O’Rourke also teaches a method of treating cancer that comprises administering this composition, as in instant claim 74. Page 58, line 8 of O’Rourke discloses that the T cells are specific to the subject, or autologous, meeting the limitations of instant claim 75. Page 58, line 12 discloses the cancer to be treated as glioblastoma, a solid tumor, meeting the limitations of instant claims 76-78.
The CAR, the cell containing the CAR, and the pharmaceutical composition containing the cell of O’Rourke have the same target as the CAR and the cell containing the CAR of ‘369 (EFGR). The CAR of ‘369 and the CAR of O’Rourke contain the same functional components and have a different EGFR-targeting scFv. However, since both the scFv of ‘369 and O’Rourke target the same molecule, and the function of the CAR remains the same, the substitution of the CAR of ‘369 for the CAR of O’Rourke in the composition and/or the method of O’Rourke would have yielded predictable results. Therefore, as MPEP 2143(I)(B) recites that simple substitution of one known element for another to obtain predictable results is obvious, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute the cell containing the CAR of ‘369 for the cell containing the CAR of O’Rourke in the composition of O’Rourke to yield the pharmaceutical composition of instant claim 73. Moreover, it would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to substitute this composition comprising the cell containing the CAR of ‘369 for the composition of O’Rourke into the method of treating cancer presented in O’Rourke in order to treat glioblastoma, thus rendering the instant invention of claims 74-78 obvious. One would have a reasonable expectation of success as the CARs of O’Rourke and ‘369 have the same target and the same functional domains, and will thus perform in a predictable manner when substituted for each other.
Conclusion
No claims are allowed.
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/AMELIA STEPHENS/ Examiner, Art Unit 1645
/DANIEL E KOLKER/ Supervisory Patent Examiner, Art Unit 1645