DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. The claim set filed 12/13/2023 is acknowledged. Claims 158- 177 are pending and under examination.
Information Disclosure Statement
3. The information disclosure statement (IDS) submitted on 06/02/2023 and 09/08/2023 and the references cited therein have been considered, unless indicated otherwise.
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.
Specification
4. The use of the term OPDIVO, KEYTRUDA, CT-011 CURE TECH, MERCK, ROCHE, LIBTAYO, TECENTRIQ, BAVENCIO, and IMFINZI, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Written Description
The following rejection is a written description rejection. The written description reject has two issues. One issue is regarding written description with amino acid variance and the use of the word “an” and the second issue is regarding the broadly claimed genus of cancers encompassed by the claimed invention.
5. First, claims 161, 164, 167, 170, 171, and 173 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
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, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, 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 Applicants were in possession of the claimed genus.
The following claims are being rejected depend on instant claim 158 which is drawn to a method for treating a cancer in a subject in need thereof the method comprising a step of administering to the subject an effective amount of a chimeric protein having a general structure of: N terminus - (a) - (b) - (c) - C terminus, wherein:(a) is a first domain comprising an extracellular domain of human T cell immunoreceptor with Ig and ITIM domains (TIGIT), (b) is a linker adjoining the first and second domains, wherein the linker comprises a hinge-CH2-CH3 Fc domain, and (c) is a second domain comprising an extracellular domain of human LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), wherein the chimeric protein is administered at a dose sufficient to induce lymphocyte expansion and/or margination, wherein the dose is between about 0.03 mg/kg and about 50.0 mg/kg. The rejected claims are drawn to a method for treating a cancer in a subject in need thereof the method comprising a step of admitting to the subject an effective amount of a chimeric protein that comprises the TIGIT domain, a linker and human LIGHT domain; wherein the first domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10; wherein the second domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2; wherein the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 112, or SEQ ID NO: 113; wherein (a) the first domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10,(b) the second domain comprises the amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2, and (c) the linker comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 112, or SEQ ID NO: 113; wherein the chimeric protein further comprises at least one joining linker comprising an amino acid sequence selected from SKYGPPCPSCP (SEQ ID NO: 49), SKYGPPCPPCP (SEQ ID NO:50), IEGRMD (SEQ ID NO:52); wherein the chimeric protein comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NO: 11, SEQ ID NO: 109, and SEQ ID NO: 110.
The specification discloses the chimeric protein that comprises the TIGIT domain, a linker and human LIGHT domain .The specification discloses a chimeric protein comprising SEQ ID NO: 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113.
There are two main issues with regards to written description of the instant claims. First, the claims encompass a genus of chimeric protein complex that are not adequately described. Although the claims are inclusive of the chimeric protein complex comprising a first domain of human TIGIT, a linker and second domain of human, the claims also broadly encompass chimeric protein complex first domain, linker and second domain of 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113 that are at least 95% identical to the full-length amino acid sequences. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 5%, for example, in the polypeptide set forth in SEQ ID NO: 2 that is 182 amino acids in length translates into 9 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 182 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 95%. Applicants have not described which domain or portions of SEQ ID NO: 2 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants and fragments) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
The second issue is the use of the term “an” when describing the fusion protein sequences, for example in claim 161 “wherein the first domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.” It is also possible, given the language of the claim which includes "an amino acid sequence", that any two amino acids in sequence would suffice to meet the limitations of the claims. Because function of protein is dependent on the presence of each specific amino acid residue, and with the possibility of added or deleted amino acids, a wide variety of polypeptides, is encompassed by the instant claim. In addition, the phrase “an amino acid sequence” allows any fragment, including any two amino acids in sequence, to be encompassed in the instant claim. This would in theory encompass any possible peptide. These peptides have no correlation between their structure and function. It is recommended that Applicant amend the language of the claim to recite “having the amino acid sequence” in all places that “an amino acid sequence” appears to overcome this issue.
Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because, while the description of an ability of the claimed protein may generically describe the protein’s function, it does not describe the protein itself. A definition by function does not suffice to define the genu because it is only an indication of what the protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of chimeric molecule complexes is highly variable (i.e., each complex would necessarily have a unique structure, See MPEP 2434), the generic description of the heterodimer is insufficient to describe the genus, Further, given the highly diverse nature of proteins, even one of skill in the art cannot envision the structure of the chimeric molecule complex only by knowing its functional characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of chimeric molecule complexes claimed only by a functional characteristic and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). The claims generically recite a chimeric protein complex. While the specification clearly sets forth a correlation between the chimeric molecule complex comprising SEQ ID NO: 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113, and the functions of being effective against cancers acquired or primary resistance to anti-PD-1 therapy, this correlation does not appear to be clearly present in the breadth of the claims. As noted above, the claims are not limited to the disclosed chimeric protein complex comprising SEQ ID NO: : 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113 and broadly encompass chimeric protein complex comprising variants and fragments of SEQ ID NO: 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a single species has been described and this is not considered to be representative of the breadth of the genus.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two 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 genu[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.") (MPEP 2163). “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).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous heterodimers had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of heterodimers claimed only by a partial structure and functional characteristic(s).
Vas-Cath Inc. v. Mahurkar, 19 U5PQ2d 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.)
With the exception of a chimeric protein complex comprising SEQ ID NO: 2, 10, 11, 46, 47, 49, 50, 52, 109, 110, 112, and 113, the skilled artisan cannot envision the detailed chemical structure of the encompassed polypeptides, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid and/or protein itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481,1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc., 107 F.3d 1565,1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
In Ariad Pharrns., Inc. v. Eh Lilly & Co., 598 F.3d 1336,1351 (Fed. Cir. 2010), the court held that a “sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize’ the members of the genus." Ariad, 598 F.Bd at 1350. “[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials,” Id. Although “functional claim language can meet the written description requirement when the art has established a correlation between structure and function," "merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genu and showing that one has invented a genus and not just a species.
Furthermore, regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920-23, 69 USPQ2d 1886, 1890-93 (Fed. Cir. 2004).
Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138,1990) who teach that replacement of a single lysine residue at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252,1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2007) teach that the prediction of protein function from sequence and structure is a difficult problem (See abstract). Although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge (See page 309). Whisstock et al. teach that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue falls. Whisstock et al. teach that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally (See pages 321-323). Given not only the teachings of Bowie et al., Lazar et al. and Burgess et al. but also the limitations and pitfalls of assigning a function to an amino acid sequence based upon similarity as taught by Whisstock, the claimed proteins could not be predicted. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the agent per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a plurality of polypeptides defined solely in terms of their function that may not have the biological functions recited in the claims. Based on the teachings of the instant specification and the prior art, one of skill in the art would not conclude that Applicant was in possession of the claimed genus of agents.
While “examples explicitly covering the full scope of the claim language” typically will not be required, a sufficient number of representative species must be included to “demonstrate that the patentee possessed the full scope of the [claimed] invention.” Lizardtech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724, 1732 (Fed. Cir. 2005).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin, 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
Second, claims 158-177 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.
The instant claims are drawn to a method for treating a cancer in a subject in need thereof the method comprising a step of administering to the subject an effective amount of a chimeric protein having a general structure of: N terminus - (a) - (b) - (c) - C terminus, wherein:(a) is a first domain comprising an extracellular domain of human T cell immunoreceptor with Ig and ITIM domains (TIGIT), (b) is a linker adjoining the first and second domains, wherein the linker comprises a hinge-CH2-CH3 Fc domain, and (c) is a second domain comprising an extracellular domain of human LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), wherein the chimeric protein is administered at a dose sufficient to induce lymphocyte expansion and/or margination, wherein the dose is between about 0.03 mg/kg and about 50.0 mg/kg.
The specification teaches that the chimeric protein complex provides benefit for methods for cancer treatment, based on, for instance, based on gene expression profiles of anti-PD-1 resistant cancers (See page 2). The specification teaches that conditions or disorders to be treated various cancers such Hodgkin's and non-Hodgkin's lymphoma, B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; or chronic myeloblastic leukemia, basal cell carcinoma, biliary tract cancer; bladder cancer; bone cancer; brain and central nervous system cancer; breast cancer; cancer of the peritoneum; cervical cancer; choriocarcinoma; colon and rectum cancer; connective tissue cancer; cancer of the digestive system; endometrial cancer; esophageal cancer; eye cancer; cancer of the head and neck; gastric cancer (including gastrointestinal cancer); glioblastoma; hepatic carcinoma; hepatoma; intra-epithelial neoplasm; kidney or renal cancer; larynx cancer; leukemia; liver cancer; lung cancer (e.g., small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung); melanoma; myeloma; neuroblastoma; oral cavity cancer (lip, tongue, mouth, and pharynx); ovarian cancer; pancreatic cancer; prostate cancer; retinoblastoma; rhabdomyosarcoma; rectal cancer; cancer of the respiratory system; salivary gland carcinoma; sarcoma; skin cancer; squamous cell cancer; stomach cancer; testicular cancer; thyroid cancer; uterine or endometrial cancer; cancer of the urinary system; vulval cancer; lymphoma including Hodgkin's and non-Hodgkin's lymphoma, as well as B-cell lymphoma (including low grade/follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade/follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia; chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; as well as other carcinomas and sarcomas; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phacomatoses, edema (e.g., that associated with brain tumors), Meigs' syndrome cancer; renal carcinoma; colorectal cancer; and adrenal cancer (see page 67 and 68)
A method for treating a cancer in a subject in need thereof the method comprising a step of administering to the subject an effective amount of a chimeric protein does not meet the written description provision of 35 U.S.C. 112, first paragraph. The claims broadly encompass treating all cancers using the aforementioned method. The binding of the human TIGIT-Fc-LIGHT chimeric protein to recombinant human Nectin-4, HVEM, recombinant targets, CHO-K1 cells, B16.F10 tumor cells, CD155/PVR, Nectin-2, Nectin-3, LTBR, DcR3, 4-11BB, however, this is not deemed to be predicative of treating all cancers using the claimed chimeric protein complex. The claims broadly encompass the use of chimeric protein complex to treat all cancers; however, the specification does not demonstrate that the protein has the function of treating all cancers. Therefore, the protein has no correlation with its function. The specification is not deemed sufficient to reasonably convey to one skilled in the art that the inventors, at the time the invention was made, had possession of a method of treating all cancers with chimeric protein complex because the genus encompasses conditions which differ from those disclosed in etiologies, molecular mechanisms, diagnostic approaches, treatment modalities, and therapeutic endpoints. Furthermore, the recited genus encompasses conditions yet to be discovered and/or characterized; therefore, the skilled artisan cannot envision preventing all the contemplated diseases encompassed by the instant 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.)
Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that:
...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d 1966.
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).
The state of the art regarding TIGITs relation to cancer is discussed by Harjunpaa, et al. (TIGIT as an emerging immune checkpoint. Clin Exp Immunol. 2020 May;200(2):108-119. doi: 10.1111/cei.13407. Epub 2019 Dec 25. PMID: 31828774; PMCID: PMC7160651). Harjunpaa, et al. TIGIT up‐regulation has been observed in various malignancies, including melanoma, breast cancer, non‐small‐cell lung carcinoma (NSCLC), colon adenocarcinoma (COAD), gastric cancer, acute myeloid leukemia (AML) and multiple myeloma (see TIGIT inhibits anti-cancer immune responses section).
Regarding the vast genus of cancers encompassed by the claims, While the state of the art is relatively high with regard to the treatment of specific cancer types, the state of the art with regards to treating all cancers with a single treatment is underdeveloped. In particular, there is no known anticancer agent that is effective against all cancer cell types. The cancer treatment art involves a very high level of unpredictability. Heppner et al. (Cancer Metastasis Review 2:5-23; 1983) discuss the heterogeneity of tumors from different tissues, as well as the same tissue. A key point made by Heppner et al. is that tumor heterogeneity contributes greatly to the sensitivity of tumors to drugs. Heppner et al. teach that as a tumor progresses to a metastatic phenotype, the susceptibility to a particular treatment can differ, and as such, makes predicting the responsiveness to treatment difficult. Additionally, Bally et al. (US Patent No. 5,595,756) stated, "Despite enormous investments of financial and human resources, no cure exists for a variety of diseases. For example, cancer remains one of the major causes of death. A number of bioactive agents have been found, to varying degrees, to be effective against tumor cells. However, the clinical use of such antitumor agents has been highly compromised because of treatment limiting toxicities (See column 1). Sporn et al. (Chemoprevention of Cancer, Carcinogenesis, Vol. 21 (2000), 525-530) teaches the magnitude of mortality of cancers and that mortalities are in fact still rising and that new approaches to a variety of different cancer are critically needed. Sporn et al. also teach that “given the genotype and phenotype heterogeneity of advanced malignant lesions as they occur in individual patients, one wonders just exactly what are the specific molecular and cellular targets for the putative cure.”
Furthermore, the art indicates the difficulties in going from in vitro to in vivo for drug development for treatment of cancers. Auerbach et al. (Cancer and Metastasis Reviews, 2000, 19: 167-172) indicate that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response. For example, the 96 well rapid screening assay for cytokinesis was developed in order to permit screening of hybridoma supernatants…In vitro tests in general have been limited by the availability of suitable sources for endothelial cells, while in vivo assays have proven difficult to quantitate, limited in feasibility, and the test sites are not typical of the in vivo reality (see p. 167, left column, 1st paragraph). Gura T (Science, 1997, 278(5340): 1041-1042) indicates that “the fundamental problem in drug discovery for cancer is that the model systems are not predictive at all” (see p. 1, 2nd paragraph). Furthermore, Gura T indicates that the results of xenograft screening turned out to be not much better than those obtained with the original models, mainly because the xenograft rumors don’t behave like naturally occurring tumors in humans—they don’t spread to other tissues, for example (see p. 2, 4th paragraph). Further, when patient’s tumor cells in Petri dishes or culture flasks and monitor the cells’ responses to various anticancer treatments, they don’t work because the cells simply fail to divide in culture, and the results cannot tell a researcher how anticancer drugs will act in the body (see p. 3, 7th paragraph). Furthermore, Jain RK (Scientific American, July 1994,58-65) indicates that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain (see p. 58, left most column, 1st paragraph). Further, Jain RK indicates that to eradicate tumors, the therapeutic agents must then disperse throughout the growths in concentrations high enough to eliminate every deadly cells…solid cancers frequently impose formidable barriers to such dispersion (see p. 58, bottom of the left most column continuing onto the top of the middle column). Jain RK indicates that there are 3 critical tasks that drugs must do to attack malignant cells in a tumor: 1) it has to make its way into a microscopic blood vessel lying near malignant cells in the tumor, 2) exit from the vessel into the surrounding matrix, and 3) migrate through the matrix to the cells. Unfortunately, tumors often develop in ways that hinder each of these steps (see p. 58, bottom of right most column). Thus, the art recognizes that going from in vitro studies to in vivo studies for cancer drug developments are difficult to achieve.
Hait (Nature Reviews/Drug Discovery, 2010, 9, pages 253-254) states that “The past three decades have seen spectacular advances in our understanding of the molecular and cellular biology of cancer. However, with a few notable exceptions, such as the treatment of chronic myeloid leukaemia with imatinib, these advances have so far not been translated into major increases in long-term survival for many cancers. Furthermore, data suggest that the overall success rate for oncology products in clinical development is -10%, and the cost of bringing a new drug to market is over US$1 billion.” (see page 253, left column, the 1st paragraph). Hait further teaches “The anticancer drug discovery process often begins with a promising target; however, there are several reasons why the eventual outcome for a particular cancer target may be disappointing. For example, the role of the target in the pathogenesis of specific human malignancies may be incompletely understood, leading to disappointing results”, “First, many targets lie within signal transduction pathways that are altered in cancer, but, owing to the complex nature of these pathways, upstream or downstream components may make modulating the target of little or no value”; “Second, target overexpression is often overrated. There are some instances in which overexpression predicts response to treatment.”; and “Another confounding factor is that cancer is more than a disease of cancer cells, as alterations in somatic or germline genomes, or both, create susceptibilities to transformational changes in cells and in the microenvironment that ultimately cooperate to form a malignant tissue. The putative role of cancer stem cells in limiting the efficacy of cancer therapeutics is also an area of intense interest. Therefore, effective treatments may require understanding and disrupting the dependencies among the multiple cellular components of malignant tissues. Single nucleotide polymorphisms in genes responsible for drug metabolism can further complicate the picture by affecting drug pharmacokinetics; for example, as with the topoisomerase inhibitor irinotecan.”, for example, page 253, Section “Understanding the target in context”. Hait also teaches “Drug effects in preclinical cancer models often do not predict clinical results, as traditional subcutaneous xenografting of human cancer cell lines onto immunocompromised mice produces ‘tumours’ that fail to recapitulate key aspects of human malignancies such as invasion and metastasis. Several improvements have been made, including orthotopic implantation and use of mice with humanized hematopoietic and immune systems. Newer genetic mouse models can also allow analyses of tumor progression from in situ through locally advanced and, in certain cases, widespread metastatic disease. However, whether or not these models will more accurately predict drug activity against human cancer remains to be determined. Other alternatives, including three-dimensional tissue culture or xenografts of fresh human biopsy specimens onto immunocompromised mice, have the potential advantage of including the human microenvironment. However, these approaches have yet to prove their value relative to their cost.”, for example, page 253, Section “Predictive models”. Furthermore, Hait teaches that “It is now widely thought that biomarkers will drive a personalized approach to cancer drug development. The aim is that they will cut costs, decrease time to approval, and limit the number of patients who are exposed to potential toxicities without a reasonable chance of benefit — as exemplified by the development of imatinib and trastuzumab. However, recent attempts at repeating these successes in other cancer types have been less successful.”, for example, page 254, Section “Stratified/personalized medicine”. The challenges facing cancer drug development are further confirmed and discussed in Gravanis et al (Chin Clin Oncol, 2014, 3, pages 1 -5). Gravanis et al teach “The generic mechanism of action for cytotoxics made the prediction of which tumor types might respond to them very difficult, if not impossible, and necessitated a ‘trial and error’ approach against many different types of tumors.” and “The most prominent change in oncology drug development in the last 20 years has been the shift from classic cytotoxics to drugs that affect signaling pathways implicated in cancer, which belong to the so called ‘targeted therapies’.”, for example, page 1, Section “From cytotoxics to targeted therapies: how far are we from truly personalized medicine?”. Gravanis et al. further teach “Although constantly progressing, an understanding of cancer biology is far from complete. The ability to develop new compounds or generate biological data predictive of the clinical situation relies on good quality basic research data, although the complexity and constantly evolving biology of the tumor may be to blame for the frequent non-reproducibility of research results. Systemic biology approaches of the -omic type still generate largely incomprehensible, mostly due to their volume, analytical data, few pieces of which are currently actionable/drug-g-able. Finally, animal models of cancer are similarly unable to predict the clinical situation (for example, page 3, right column, the 2nd paragraph).
Beans (PNAS 2018; 115(50): 12539-12543) teaches that across cancer types, 90% of cancer deaths are caused not by the primary tumor but by metastasis. Beans teaches that although some drugs may shrink metastases along with primary tumors, no existing drugs treat or prevent metastasis directly (See page 12540). Beans states “Without a targeted approach, metastatic tumors often reemerge. “We shrink them, we send them back to their residual state, and they reenact those survival functions and retention of regenerative powers that made them metastasis-initiating cells in the first place” (See page 12540). Beans teaches that one of the major scientific challenges of studying metastatic disease is that different forms of cancer seem to metastasize through different mechanisms and the same form of cancer may metastasize differently in different subsets of patients (See page 12542). Of note, Beans states “It’s unlikely that one researcher is going to find one pathway that proves to be the key to metastasis” (See page 12542). Bean also teaches that translating many findings into therapies also presents unique hurdles in that it is difficult to measure the effectiveness of the therapy. Secondary tumors are often minuscule, and therefore, measuring success by tumor shrinkage may not work. Measuring the incidence of metastasis after treatment is also more difficult (See page 12542).
Given Bally et al teaching of treatment-limiting toxicities in clinical use; Sporn's teaching that the cancer progression is heterogeneous as it progresses, both in genotype and phenotype; Auerbach et al teaching that one of the major problems in angiogenesis research has been the difficulty of finding suitable methods for assessing the angiogenic response; Gura's teaching that the models are unpredictable; Jain's teaching that the existing pharmacopoeia has not markedly reduced the number of deaths caused by the most common solid tumors in adults, among them cancers of the lung, breast, colon, rectum, prostate and brain; both Hait and Gravanis et al teaching various challenges facing cancer drug development, such as an understanding of cancer biology is far from complete, drug effects in preclinical cancer models often do not predict clinical results and many others; and Beans teachings that the field is highly underdeveloped with regards to preventing and treating cancer metastasis; the cited references demonstrate that the treatment of cancer is highly unpredictable, if even possible for many cancers.
Accordingly, one of skill in the art would conclude that the claimed invention encompasses a broad genus of cancers that may not respond to treatment with the chimeric protein complex. The specification demonstrates that the chimeric protein complex binds to recombinant human Nectin-4, HVEM, recombinant targets, CHO-K1 cells, B16.F10 tumor cells, CD155/PVR, Nectin-2, Nectin-3, LTBR, DcR3, 4-11BB. While the prior art demonstrates that TIGIT is effective against including melanoma, breast cancer, non‐small‐cell lung carcinoma (NSCLC), colon adenocarcinoma (COAD), gastric cancer, acute myeloid leukemia (AML) and multiple myeloma, one of skill in the art would not deem the prior art in to be predicative of the efficacy of the claimed chimeric protein complex. Based on the teaching of the instant specification and the prior art one of skill in the art would not conclude that Applicant was in possession of the claimed method of treating the genus of cancers.
Consequently, the method for treating all cancers comprising administering chimeric protein, does not meet the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. The applicant has not disclosed any species representative of the genus, which is highly variant. Applicant is reminded that Vas- Cath makes clear that the written description provision of 5 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is severable from its enablement provision. (See page 1115).
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.
6. Claims 161, 164, 167, 170, 171, and 173 is 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 161 recites “…wherein the first domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10.” The use of “an amino acid sequence” encompasses amino acids that comprise the full-length sequence of SEQ ID NO: 10 or any portion of SEQ ID NO: 10. Given the broadest reasonable interpretation, the claimed method would encompass administering the full-length amino acid sequence set forth in SEQ ID NO: 10 or any portion of SEQ ID NO: 10. However, the specification provides no guidance regarding the specific portion(s) of SEQ ID NO: 10 that would maintain the chimeric protein complex function. Thus, there is ambiguity as to the scope of the claim and one of skill in the art would not be apprised of the scope of the claim. Clarification and/or correction is required.
It is suggested that Applicant amend the claim as follows for clarity and precision of claim language: The method of claim 158, wherein the first domain comprises the amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10. Appropriate correction is required for the rest of the rejected claims.
7. The term/phrase “substantially”, “capable of”, “derived from” and “believed to be resistant” in claims 159, 160, 162, 163, 165, and 176 are relative terms which renders the claims indefinite. The term “substantially”, “capable of”, “derived from” and “believed to be resistant” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The word/phrase introduces a range of possibilities and even wider in some interpretations which causes ambiguity. The rationale for avoiding such phrasing comes down to accuracy, reproducibility and the proper representation of uncertainty.
Double Patenting
8. 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.
9. Claims 158-166, 168, 169, 171, 173 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 3, 5, 6, 8, 11 of Schreiber, et. al. (U.S. Patent No. 10,899,817 B2; Issued 01/26/2021).
Instant claim 158, 161, and 164 recites a method for treating a cancer in a subject in need thereof the method comprising a step of administering to the subject an effective amount of a chimeric protein having a general structure of:N terminus - (a) - (b) - (c) - C terminus, wherein:(a) is a first domain comprising an extracellular domain of human T cell immunoreceptor with Ig and ITIM domains (TIGIT), (b) is a linker adjoining the first and second domains, wherein the linker comprises a hinge-CH2-CH3 Fc domain, and (c) is a second domain comprising an extracellular domain of human LIGHT (lymphotoxin-like, exhibits inducible expression and competes with HSV glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes), wherein the chimeric protein is administered at a dose sufficient to induce lymphocyte expansion and/or margination, wherein the dose is between about 0.03 mg/kg and about 50.0 mg/kg; wherein the first domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 10; wherein the second domain comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 2.
Instant claims 158, 161 and 164 are rejected over multiple claims of Schreiber, et al. which are claims 1 and 5 that teach the method of treating cancer comprising administering a chimeric protein of a general structure of: N terminus - (a) - (b) - (c) - C terminus, identical to the one discussed in instant claim 158. Wherein the first domain comprising an extracellular domain of TIGIT, a linker and a second domain comprising an extracellular domain of LIGHT. The TIGIT domain and LIGHT domain discussed in Schreiber, et al. are attributed the amino acid sequence of having at least 95% identical to the amino acid sequence of SEQ ID NO: 10 and 2. The sequences, TIGIT domain having at least 95% identical to the amino acid sequence of SEQ ID NO: 10 and LIGHT domain having at least 95% identical to the amino acid sequence of SEQ ID NO: 2, are 100% identical to sequences discussed in instant claim 161 and 164: TIGIT domain having the amino acid sequence of SEQ ID NO: 10 and the LIGHT domain having the amino acid sequence of SEQ ID NO: 2. Schreiber, et al. teach in claim 5 the linker comprises a hinge-CH2-CH3 Fc domain derived from IgG1 or IgG4, which is the same linker discussed in instant claim 1
Schreiber SEQ ID NO: 10 is 100% identical to instant SEQ ID NO: 10.
Query Match 100.0%; Score 637; DB 1; Length 120;
Best Local Similarity 100.0%;
Matches 120; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF 60
Qy 61 KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP 120
Schreiber SEQ ID NO: 2 is 100% identical to instant SEQ ID NO: 2.
Query Match 100.0%; Score 959; DB 1; Length 182;
Best Local Similarity 100.0%;
Matches 182; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 LQLHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 LQLHWRLGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQL 60
Qy 61 GLAFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELE 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GLAFLRGLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELE 120
Qy 121 LLVSQQSPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAF 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 LLVSQQSPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAF 180
Qy 181 MV 182
||
Db 181 MV 182
Instant claim 158, 165 and 166 describes the linker that adjoins the first and second domains, wherein the linker comprises a hinge-CH2-CH3-Fc domain; wherein the linker comprises a hinge-CH2-CH3 Fc domain derived from IgG1 or IgG4; wherein the hinge-CH2-CH3 Fc domain is derived from human IgG1 or human IgG4.
Instant claims 158, 165 and 166 are rejected over multiple claims of Schreiber, et al. which are claims 1 that was discussed in the second paragraph, and 5 and 6 that describes the same linker: wherein the linker comprises a hinge-CH2-CH3 Fc domain derived from IgG1 or IgG4; wherein the hinge-CH2-CH3 Fc domain is derived from human IgG1 or human IgG4.
Instant claim 159 recites: the method of claim 158, wherein the first domain is capable of binding a TIGIT ligand. Schreiber, et al. teach the same capability of the first domain recites in claim 2: wherein the first domain is capable of binding a TIGIT ligand selected from CD155/PVR, Nectin-2, Nectin-3, and Nectin-4.
Instant claim 160 recites: the method of claim 158, wherein the first domain comprises substantially all of the extracellular domain of TIGIT. Schreiber, et al. teach in claim 1 that the first domain is comprising an extracellular domain of TIGIT. Instant claim 160 is anticipated by claim 1 of Schreiber, as the first domain comprising of an extracellular domain of TIGIT is comprising substantially all of the extracellular domain of TIGIT.
Instant claim 162 recites: the method of claim 158, wherein the second domain is capable of binding a LIGHT receptor. Schreiber, et al. teach the same capability of the second domain recites in claim 3: wherein the second domain is capable of binding a LIGHT ligand selected from LTBR, HVEM, and DcR3.
Instant claim 163 recites: the method of claim 158, wherein the second domain comprises substantially all of the extracellular domain of LIGHT. Schreiber, et al. teach in claim 1 that the second domain is comprising of an extracellular domain of LIGHT. Instant claim 163 is anticipated by claim of Schreiber, as the second domain comprising of an extracellular domain of light is comprising substantially all of the extracellular domain of LIGHT.
Instant claim 168, 169, and 171 recite: the method of claim 158, wherein the linker comprises one or more joining linkers, such joining linkers independently selected from SEQ ID NOs: 49-95; wherein the linker comprises two or more joining linkers each joining linker independently selected from SEQ ID NOs: 49-95; wherein one joining linker is N terminal to the hinge- CH2-CH3 Fc domain and another joining linker is C terminal to the hinge-CH2-CH3 Fc domain; wherein the chimeric protein further comprises at least one joining linker comprising an amino acid sequence selected from SKYGPPCPSCP (SEQ ID NO: 49), SKYGPPCPPCP (SEQ ID NO:50), IEGRMD (SEQ ID NO:52). Schreiber, et al. recites in claim 8: the method of claim 5 wherein the linker comprises one or more joining linkers, such joining linkers being independently selected from SEQ ID NOs: 49-95, optionally: wherein the linker comprises two or more joining linkers each joining linker independently selected from SEQ ID NOs: 49-95; wherein one joining linker is N terminal to the hinge-CH2-CH3 Fc domain and another joining linker is C terminal to the hinge-CH2-CH3 Fc domain. Instant SEQ ID NO: 49-95 is 100% to Schreiber SEQ ID NO: 49-95. This also includes the sequences in instant claim 171, where the linker is comprised of amino acid sequence of SEQ ID NO: 49, 50 and 52.
Instant claim 173 recites: the method of claim 158, wherein the chimeric protein comprises an amino acid sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NO: 11, SEQ ID NO: 109, and SEQ ID NO: 110. Schreiber, et al. recites in claim 11: the method of claim 1, wherein the chimeric protein has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 11. Instant SEQ ID NO: 11, 100% identical to Schreiber SEQ ID NO: 11.
Query Match 100.0%; Score 2857; Length 536;
Best Local Similarity 100.0%;
Matches 536; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSF 60
Qy 61 KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 KDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIP 120
Qy 121 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYV 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SKYGPPCPPCPAPEFLGGPSVFLFPPKPKDQLMISRTPEVTCVVVDVSQEDPEVQFNWYV 180
Qy 181 DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 DGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLSGKEYKCKVSSKGLPSSIEKTISNA 240
Qy 241 TGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLD 300
Qy 301 SDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKIEGRMDLQLHWR 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHNHYTQKSLSLSLGKIEGRMDLQLHWR 360
Qy 361 LGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQLGLAFLR 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 LGEMVTRLPDGPAGSWEQLIQERRSHEVNPAAHLTGANSSLTGSGGPLLWETQLGLAFLR 420
Qy 421 GLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELELLVSQQ 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 GLSYHDGALVVTKAGYYYIYSKVQLGGVGCPLGLASTITHGLYKRTPRYPEELELLVSQQ 480
Qy 481 SPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAFMV 536
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 SPCGRATSSSRVWWDSSFLGGVVHLEAGEKVVVRVLDERLVRLRDGTRSYFGAFMV 536
Conclusion
10. No claims are allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Syed J Abbas whose telephone number is (571)272-0015. The examiner can normally be reached M-Th, 9:00AM-4:00PM.
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/SYED J ABBAS/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674