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 .
Election/Restrictions
2. Applicant’s election without traverse of a single species which read on claims 1-2, 5, 9, 12, 14-15, 17, 20, 22-23, 26, 28, 36-38, 49-50, and 52-53 ((A) Extracellular Target Molecule Binding Domain: a. SEQ ID NO: 1; B) Intracellular Activation Signaling Domain: a. SEQ ID NO: 42; C) Intracellular Detection Signaling Domain: a. SEQ ID NO: 20; D) Transmembrane Domain: a. SEQ ID NO: 12; E) Intracellular Spacer Domain: a. SEQ ID NO: 54; F) Intracellular Linker Domain: a. SEQ ID NO: 58; G) Extracellular Spacer Domain: a. SEQ ID NO: 16;) in the reply filed on 10/22/2025 is acknowledged.
3. The election without traverse filed 10/22/2025 is acknowledged. Claims 3-4, 6-8, 10-11, 13, 16, 18-19, 21, 24-25, 27, 29-35, 39-48, 51, and 54-67 are canceled. Claims 1-2, 5, 9, 12, 14-15, 17, 20, 22-23, 26, 28, 36-38, 49-50, and 52-53 are pending and under examination.
Information Disclosure Statement
4. The information disclosure statements (IDS) submitted 06/26/2023, 10/11/2024, and 3/18/2025 and the references cited therein have been considered, unless indicated otherwise.
Specification
5. The use of the term Opdivo (page 265), Nivolumab (page 265), Keytruda (page 265), and Erbitux (page 257) which are a trade name or a mark used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms 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.
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.
Written Description
The following rejection is a written description rejection. This written description rejection has two issues. One issue regarding written description with regard to the claimed method using the term “an amino acid sequence” and the other issue is regarding the claimed method using “fragment” language.
6. First, claims 1-2, 5, 9, 12, 15, 17, 20, and 28 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. Please note that claim 1 is rejected in this rejection because it is a claim that claims 2, 5, 9, 12, 15, 17, 20, 26, and 28 depend on. The issue is specifically regarding the claimed method using the term “an amino acid sequence”. 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 instant claims are drawn to a chimeric antigen receptor; wherein the intracellular activation signaling domain is an amino acid sequence comprising SEQ ID NO: 42; wherein the intracellular detection signaling domain is an amino acid sequence comprising SEQ ID NO: 20; wherein the extracellular target molecule binding domain is an amino acid sequence comprising SEQ ID NO: 1; wherein the transmembrane domain is an amino acid sequence comprising SEQ ID NO: 12; wherein the extracellular spacer domain is an amino acid sequence comprising SEQ ID NO: 16; wherein the intracellular spacer domain is an amino acid sequence comprising SEQ ID NO: 54; wherein the intracellular linker domain is an amino acid sequence comprising SEQ ID NO: 58.
The specification discloses the chimeric antigen receptor and the domains within. The specification discloses the amino acid sequences for the specific domains.
The main issue is the use of the term “an” when describing the chimeric antigen receptor domain sequences, for example in claim 1 “the intracellular activation signaling domain is an amino acid sequence comprising SEQ ID NO: 42.” 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 antigen receptor complexes is highly variable (i.e., each complex would necessarily have a unique structure, See MPEP 2434), the generic description of the CAR 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 CAR 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 antigen receptor. As noted above, the claims are not limited to the disclosed chimeric antigen receptor comprising SEQ ID NO: 1, 12, 16, 20, 42, 54 and 58 and broadly encompass chimeric antigen receptor complexes comprising variants and fragments of SEQ ID NO: 1, 12, 16, 20, 42, 54 and 58 . 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.)
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).
Secondly, claims 1-2, 5, 9, 12, 14-15, 17, 20, 22-23, 26, 28, 36-38, 49-50, and 52-53 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. Please note that claims 12, 14, 15, 17, 20, 22, 23, 26, 28, 36, 49-50, and 52-53 are rejected in this rejection because they depend on independent claim 1. The issue is specially regarding with the claimed genus of fragment. 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 instant claims are drawn to a chimeric antigen receptor, comprising: a) an extracellular target molecule binding domain for specifically binding to a target molecule; b) an intracellular signaling domain comprising at least one intracellular activation signaling domain and/or at least one intracellular detection signaling domain; and c) a transmembrane domain, used to connect the extracellular target molecule binding domain and the intracellular signaling domain, and to anchor the extracellular target molecule binding domain and the intracellular signaling domain on a cell membrane; wherein, an activation of the intracellular activation signaling domain at least relies on a binding of the extracellular target molecule binding domain to the target molecule; and the intracellular activation signaling domain comprises a molecule or a fragment comprising a catalytic domain; wherein the intracellular detection signaling domain comprises at least one immunoreceptor tyrosine-based activation motif ITAM; preferably, the intracellular detection signaling domain is at least one of CD3( ITAMI fragment, CD3( ITAM2 fragment, CD3( ITAM3 fragment, FcRIIA ITAM fragment, FcRy ITAM fragment, DAP12 ITAM fragment, and CD3e ITAM fragment; preferably, the intracellular detection signaling domain comprises at least one signaling domain of a molecule selected from 2B4, CD244, BTLA, CD36, CD37, CD3; wherein the target molecule bound by the extracellular target molecule binding domain comprises at least one of the following molecules: immunosuppressive signal-related molecule, tumor surface antigen molecular marker, and specific antigen peptide- histocompatibility complex molecule on cell surface; preferably, the extracellular target molecule binding domain comprises at least one of target molecule binding domain of a molecule selected from PD-1, truncated PD-1, PD-1 variant, antibody against PD-L1, and PD-L1-binding fragment; preferably, the extracellular target molecule binding domain comprises at least one of an amino acid sequence comprising SEQ ID NO: 001, an amino acid sequence comprising SEQ ID NO: 003, an amino acid sequence comprising SEQ ID NO: 005, an amino acid sequence comprising SEQ ID NO: 007, an amino acid sequence comprising SEQ ID NO: 009, and an amino acid sequence comprising SEQ ID NO: 011; wherein the nucleic acid molecule comprises at least one of an extracellular target molecule binding domain nucleic acid fragment, a transmembrane domain nucleic acid fragment, an intracellular activation signaling domain nucleic acid fragment, an extracellular spacer domain nucleic acid fragment, an intracellular detection signaling nucleic acid fragment, an intracellular spacer domain nucleic acid fragment, and an intracellular linker domain nucleic acid fragment; wherein the extracellular target molecule binding domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 002, a nucleic acid sequence comprising SEQ ID NO: 004, a nucleic acid sequence comprising SEQ ID NO: 006, a nucleic acid sequence comprising SEQ ID NO: 008, and a nucleic acid sequence comprising SEQ ID NO: 010; preferably, the transmembrane domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 013 and a nucleic acid sequence comprising SEQ ID NO:015; preferably, the intracellular activation signaling domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 043, a nucleic acid sequence comprising SEQ ID NO: 045, a nucleic acid sequence comprising SEQ ID NO: 047, a nucleic acid sequence comprising SEQ ID NO: 049, a nucleic acid sequence comprising SEQ ID NO: 051, and a nucleic acid sequence comprising SEQ ID NO: 053; preferably, the extracellular spacer domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 017 and a nucleic acid sequence comprising SEQ ID NO: 019; preferably, the intracellular detection signaling domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 021, a nucleic acid sequence comprising SEQ ID NO: 023, a nucleic acid sequence comprising SEQ ID NO: 025, a nucleic acid sequence comprising SEQ ID NO: 027, a nucleic acid sequence comprising SEQ ID NO: 029, a nucleic acid sequence comprising SEQ ID NO: 031, a nucleic acid sequence comprising SEQ ID NO: 033, a nucleic acid sequence comprising SEQ ID NO: 035, a nucleic acid sequence comprising SEQ ID NO: 037, a nucleic acid sequence comprising SEQ ID NO: 039, and a nucleic acid sequence comprising SEQ ID NO:041; preferably, the intracellular spacer domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 055 and a nucleic acid sequence comprising SEQ ID NO: 057;preferably, the intracellular linker domain nucleic acid fragment comprises at least one of a nucleic acid sequence comprising SEQ ID NO: 059, a nucleic acid sequence comprising SEQ ID NO: 061, a nucleic acid sequence comprising SEQ ID NO: 063, and a nucleic acid sequence comprising SEQ ID NO: 065.
The specification teaches the composition of CAR molecules mainly includes: the extracellular antigen recognition domain from antigen-specific single-chain antibody fragment, the spacer domain between the antigen recognition domain and the transmembrane domain from molecular linker fragments such as IgG family proteins, transmembrane domain from molecular transmembrane fragment such as CD28 or CD8, the intracellular co-stimulatory signaling domain and the intracellular activation signaling domain (page 6). The specification teaches the intracellular activation signaling domain contains a molecule or a fragment having a catalytic domain (page 8). The specification teaches intracellular detection signaling domain is at least one of CD3( ITAMI fragment, CD3( ITAM2 fragment, CD3( ITAM3 fragment, FcRIIA ITAM fragment, FcRy ITAM fragment, DAP12 ITAM fragment, and CD3s ITAM fragment (page 9).
The issue with regard to the written description provision is that the genus of fragment is not adequately described. The claims also broadly encompass fragment. The specification provides no guidance regarding which amino acids can be modified in the fragment, while maintaining any given function. Therefore, these structures (i.e., different forms) 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).
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). While the specification clearly sets forth a correlation between the claimed fragment, and the claimed functions, 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 fragment. 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 one species has been described and this is not considered to be representative of the breadth of the genus. Therefore, given the lack of structure function correlation and the lack of a representative number of species, the specification provides insufficient written description to support the genus encompassed by the claim.
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.)
The skilled artisan cannot envision the detailed chemical structure of the encompassed fragment, 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.
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. Punta et al. (PLoS Comput Biol 4(10): e1000160, 2008) teach that homology (both orthology and paralogy) does not guarantee conservation of function (See page 2). Punta et al. teach that relatively small difference in sequence can sometimes cause quite radical changes in functional properties, such as a change of enzymatic action, or even loss or acquisition of enzymatic activity itself (See page 2). Punta et al. teach that it is also apparent that there is no sequence similarity threshold that guarantees that two proteins share the same function (see page 2). Punta et al. teach that homology between two proteins does not guarantee that they have the same function, not even when sequence similarity is very high (including 100% sequence identity) (See page 2 and table 2). Punta et al. teach that proteins live and function in 3D, and therefore structural information is very helpful for predicating function (See page 4). However, as with sequence, two proteins having the same overall architecture, and even conserved functional residues, can have unrelated functions (See page 4). Punta et al. teach that still; structural knowledge is an extremely powerful tool for computational function prediction (See page 5).
Similarly, 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 moreover, even closely related proteins can change function, either through divergence to a related function or by recruitment for a very different function (See page 309). Further, Whisstock et al. note that in some instances, even sequences that are the same can have different functions. For example, eye lens proteins in the suck are identical in sequence to active lactate dehydrogenase and enolase in other tissues, although they do not encounter the substrates in the eye (See page 310). 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 fall (See page 321). 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).
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 reside 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 Song et al. (Molecular Biology of the Cell, 15:1287–1296, March 2004) who teach that substitution of alanine for aspartate in surviving results in the conversion of surviving’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that polypeptide or a variant that shares only partial homology with a disclosed protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the proteins 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.
Applicant is reminded that generally, 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 (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai 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.
The 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 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the 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 Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and 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. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claim Rejections - 35 USC § 102
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.
7. Claims 1 and 49 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Juno Therapeutics, INC (referred as Juno hereinafter) (WO 2017/079705 A1, published 11 May 2017).
The instant claims are drawn to a chimeric antigen receptor, comprising: a) an extracellular target molecule binding domain for specifically binding to a target molecule; b) an intracellular signaling domain comprising at least one intracellular activation signaling domain and/or at least one intracellular detection signaling domain; and c) a transmembrane domain, used to connect the extracellular target molecule binding domain and the intracellular signaling domain, and to anchor the extracellular target molecule binding domain and the intracellular signaling domain on a cell membrane; wherein, an activation of the intracellular activation signaling domain at least relies on a binding of the extracellular target molecule binding domain to the target molecule; and the intracellular activation signaling domain comprises a molecule or a fragment comprising a catalytic domain and a pharmaceutical composition, comprising the chimeric antigen receptor according to claim 1.
Juno teach a chimeric receptor comprising a ligand-biding domain, a transmembrane domain, and an intracellular signaling domain comprising a signaling domain derived from human CD40 (claim 1). The ligand-binding domain is the same entity as the extracellular target molecule binding domain. Juno teach the ligand-binding domain comprises an antigen-binding (claim 20) that specifically can bind multiple target molecules including CD19, CD20, and CD22 (claim 29). Juno teach the transmembrane domain links the ligand-binding domain and the intracellular signaling domain (paragraph 30). Juno teach a TCR containing constant domains with a transmembrane region can anchor the protein in the cell membrane (paragraph 113). Juno teach among the compositions are pharmaceutical compositions and formulations for administration (paragraph 174).
Thus, Juno anticipate the claimed invention of claim 1 and 49.
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.
8. Claims 1-2, 5, 9, 12, 15, 17, 20, 28, 38, 49, and 52 are rejected under 35 U.S.C. 103 as being unpatentable by Juno Therapeutics, INC (referred as Juno hereinafter) (WO 2017/079705 A1, published 11 May 2017) in view of Zhao, et al. (US 10780120 B2, filed 5 March 2019).
The instant claims are drawn to a chimeric antigen receptor, comprising: a) an extracellular target molecule binding domain for specifically binding to a target molecule; b) an intracellular signaling domain comprising at least one intracellular activation signaling domain and/or at least one intracellular detection signaling domain; and c) a transmembrane domain, used to connect the extracellular target molecule binding domain and the intracellular signaling domain, and to anchor the extracellular target molecule binding domain and the intracellular signaling domain on a cell membrane; wherein, an activation of the intracellular activation signaling domain at least relies on a binding of the extracellular target molecule binding domain to the target molecule; and the intracellular activation signaling domain comprises a molecule or a fragment comprising a catalytic domain and a pharmaceutical composition, comprising the chimeric antigen receptor according to claim 1.
Juno teach a chimeric receptor comprising a ligand-binding domain, a transmembrane domain, and an intracellular signaling domain comprising a signaling domain derived from human CD40 (claim 1). The ligand-binding domain is the same entity as the extracellular target molecule binding domain. Juno teach the ligand-binding domain comprises an antigen-binding (claim 20) that specifically can bind multiple target molecules including CD19, CD20, and CD22 (claim 29). Juno teach the transmembrane domain links the ligand-binding domain and the intracellular signaling domain (paragraph 30). Juno teach a TCR containing constant domains with a transmembrane region can anchor the protein in the cell membrane (paragraph 113). Juno teach among the compositions are pharmaceutical compositions and formulations for administration (paragraph 174). Thus, Juno anticipate the claimed invention of claim 1 and 49.
Juno does not teach the chimeric receptor containing all the sequences of the elected species.
However, Zhou, et al. teach chimeric antigen receptor of SEQ ID NO: 227 that is a fusion protein of all the sequences combined of the elected species. It is noted that the instant claims recite an amino acid sequence and these do not read on the full length of the elected sequences. See the 112(a) rejection above.
Query Match 18.2%; Score 807; Length 741;
Best Local Similarity 22.3%;
Matches 238; Conservative 41; Mismatches 127; Indels 660; Gaps 33;
Qy 1 PPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDC 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 34 PPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDC 93
Qy 61 RFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEPDP 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||| |
Db 94 RFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEV-P 152
Qy 121 AAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFPIERQ 180
||
Db 153 TAH--------------------------------------------------------- 155
Qy 181 LNGTYAIA GGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRDAMVR 240
| ||:|
Db 156 ----------------------------------PSPSPRPAG----------------- 164
Qy 241 DYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSGAQTD 300
Db 165 ------------------------------------------------------------ 164
Qy 301 GKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTL--WQLVEYLKLK 358
:| || | ||
Db 165 -------------------------------------------QFQTLVFWVLV-----V 176
Qy 359 ADGLIYCL---------------KEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTL 403
|:: | | | | | | :
Db 177 VGGVLACYSLLVTVAFIIFWVRSKR----------------------SRLLHS----DYM 210
Qy 404 NSDGYTPEPARITSPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCG 463
| :| :| | | : ||: | :
Db 211 N-----------MTPRRPGP----TRKHYQPYAPPRDF---------------------- 233
Qy 464 NFGSVRQGVYRMRKKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQA 523
|| |: : | :::| | ::
Db 234 -------AAYRSVKQTL------------------------------NFDLLKLAGDVES 256
Qy 524 E---------ALMLVMEMAGGGPLHKFLVGKREEI-------PVSNVAELLHQVSMGMKY 567
||:| || | | |: | | | | |
Db 257 NPGPMALPVTALLL--------PLALLLHAARPEVQLVQSGAEVKKPGESLKISCKGSGY 308
Qy 568 LEEKNFVH--RDLAARNVLLVNRHYAKISDFGLSKA------LGADDS------------ 607
|:: | : : : : | || | : : || |
Db 309 SFTSNWIGWVRQMPGKGLEWMGIIYPGDSDTRYSPSFQGQVTISADKSISTAYLQWNSLK 368
Qy 608 ------YYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYG------------------- 642
|| || | | |:| |
Db 369 ASDTAMYYCARQTG----------------FLWSFDLWGRGTLVTVSSGGGGSGGGGSGG 412
Qy 643 ---------------------VTM-------------WEALSYGQKPYKKMK-------- 660
||: | | ||| | |
Db 413 GGSAIQLTQSPSSLSASVGDRVTITCRASQDISSALAW----YQQKPGKAPKLLIYDASS 468
Qy 661 -------------------------GPEVMA--FIEQ----------GKRMEC------- 676
|| | : :| | ::|
Db 469 LESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPLTFGGGTKVEIKIKTTTP 528
Qy 677 -------------------PPECPPE-----------------------------LYALM 688
| | | : :
Db 529 APRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDFWLPIGCAAFVVVCILGCI 588
Qy 689 SDCWIYKWEDRPDFLTVEQRMRACYYSLASKVEGPPGS---------------------- 726
||: | : || | | | |
Db 589 LICWLTKKK----------------YS--SSVHDPNGEYMFMRAVNTAKKSRLTDVTLRV 630
Qy 727 --TQKAEAAC----ANQLYNELNLGRREEYDVLDKVGVVGGLLGSLVLLVWVLAVICSRA 780
:: |:| |||||||||||||||||||| |
Db 631 KFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDK-----------------------RR 667
Qy 781 AR----------------------------------GTIGARRTGQ 792
| | | || |:
Db 668 GRDPEMGGKPQRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGK 713
Conclusion
9. No claims are allowed.
10. 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
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