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 .
Claims Status
2. The preliminary amendment filed 12/18/2023 is acknowledged. Claims 13-15 are new. Claims 3 and 8 are amended. Claims 1-15 are pending and under examination.
Information Disclosure Statement
3. 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
4. The use of the term R&D Systems (page 86), 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. Please review the specification for other Trademarks and correction is required.
Claim Objections
5. The claims 8 and 15 are objected to because they include the word “specified” enclosed within parentheses. This is not necessary and appropriate correction is required.
6. Claims 10 and 12 are objected to because of the following informalities: the claims recite “iPS” which contain acronyms and/or abbreviations that should be spelled out upon first occurrence. . Appropriate correction is required
7. Claims 2-8, 10-15 are objected to because of the following informalities: the word “Claim” should not be capitalized. Appropriate correction is required
Claim Rejections - 35 USC § 112
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 7, 8, and 15 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 7, 8 and 15 recites “an amino acid sequence.” The use of “an amino acid sequence” encompasses amino acids that comprise the full-length sequence of SEQ ID NO: 29 or 30 or any portion of SEQ ID NO: 29 or 30. Given the broadest reasonable interpretation, the claimed method would encompass administering the full-length amino acid sequence set forth in SEQ ID NO: 29 and 30 or any portion of SEQ ID NO: 29 and 30. However, the specification provides no guidance regarding the specific portion(s) of SEQ ID NO: 29 and 30 that would maintain the 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 amino acid sequence”.
7. Claims 2, 5 and 6 are rejected for being indefinite. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2, 5 and 6 recites the broad recitation “or less” and “or higher”. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such broad language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. It is unclear what the upper or lower limit is to the claims.
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.
The following rejection is a written description rejection. This written description rejection has two issues. One issue regarding the use of the phrase “an amino acid sequence” and the other is regarding lack of antibody structure.
8. First, claims 7, 8, and 15 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 instant claims are drawn to a receptor tyrosine kinase agonist comprising a single-domain antibody having a cell growth activity, wherein the receptor tyrosine kinase agonist is at least one receptor tyrosine kinase agonist selected from the group consisting of a human fibroblast growth factor receptor 1 (FGFR1), a human fibroblast growth factor receptor 2 (FGFR2), a human fibroblast growth factor receptor 3 (FGFR3), and a human fibroblast growth factor receptor 4 (FGFR4); the receptor tyrosine kinase agonist according to claim 1 wherein an amino acid sequence of a complementarity determining region (CDR) of the single-domain antibody includes an amino acid sequence represented by SEQ ID NO: 29 or an amino acid sequence represented by SEQ ID NO: 30; the receptor tyrosine kinase agonist according to claim 1 wherein the single-domain antibody includes an amino acid having characteristics of any one of the following (1) to (5) at a position defined (specified) according to Kabat numbering: (1) a 37th amino acid is any amino acid selected from the group consisting of tyrosine (Y), phenylalanine (F), and valine (V), (2) a 41st amino acid is proline (P), (3) a 44th amino acid is any amino acid selected from the group consisting of glutamine (Q), glycine (G), glutamic acid (E), and lysine (K),(4) a 45th amino acid is arginine (R) or leucine (L), and (5) a 47th amino acid is any amino acid selected from the group consisting of leucine (L), alanine (A), tryptophan (W), glycine (G), and phenylalanine (F); the receptor tyrosine kinase agonist according to claim 2 wherein the single-domain antibody includes an amino acid having characteristics of any one of the following (1) to (5) at a position defined (specified) according to Kabat numbering: (1) a 37th amino acid is any amino acid selected from the group consisting of tyrosine (Y), phenylalanine (F), and valine (V), (2) a 41st amino acid is proline (P), (3) a 44th amino acid is any amino acid selected from the group consisting of glutamine (Q), glycine (G), glutamic acid (E), and lysine (K), (4) a 45th amino acid is arginine (R) or leucine (L), and (5) a 47th amino acid is any amino acid selected from the group consisting of leucine (L), alanine (A), tryptophan (W), glycine (G), and phenylalanine (F).
The specification discloses the amino acid sequence of a complementarity determining region (CDR) of the single-domain antibody preferably includes an amino acid sequence represented by SEQ ID NO: 29 or an amino acid sequence represented by SEQ ID NO: 30 (page 6).
The issue is the use of the term “an” when describing the agonist sequences, for example in claim 7 “wherein an amino acid sequence of a CDR of the single domain antibody in includes an amino sequence represented by SEQ ID NO 29 and 30.” 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.
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 molecule complex comprising SEQ ID NO:1 and SEQ ID NO:2, 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 1-15 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is drawn to a receptor tyrosine kinase agonist comprising a single-domain antibody having a cell growth activity, wherein the receptor tyrosine kinase agonist is at least one receptor tyrosine kinase agonist selected from the group consisting of a human fibroblast growth factor receptor 1 (FGFR1), a human fibroblast growth factor receptor 2 (FGFR2), a human fibroblast growth factor receptor 3 (FGFR3), and a human fibroblast growth factor receptor 4 (FGFR4)
Claim 7 encompass a genus of single domain antibodies comprising one CDR with two amino acid sequences. Thus, the claims encompass a vast genus of antibodies and variants thereof comprising one CDR.
Claims 8 and 15 further limit the antibody to include having characteristics of having multiple substitutions at positions 37, 41 ,44 ,45 and 47.
The instant specification recites the amino acid sequence of a complementarity determining region (CDR) of the single-domain antibody preferably includes an amino acid sequence represented by SEQ ID NO: 29 or an amino acid sequence represented by SEQ ID NO: 30 (page 6). The specification teaches the receptor tyrosine kinase agonist is preferably derived from a gene of a heavy-chain antibody of an animal of the family Camelidae or cartilaginous fish. The specification teaches an antibody, which lacks an L chain and is composed only of an H chain, found in an animal of the family Camelidae and cartilaginous fish, is referred to as a "heavy-chain antibody" or a "single heavy-chain antibody". Here, the single heavy chain means consisting of only a heavy chain and not forming a double chain of a heavy chain and a light chain as in the immunoglobulin. It is a single chain rather than a double chain even in a case where two heavy chains form a dimer by, for example, a disulfide bond (page 24). The specification teaches Human- and mouse-derived VH regions, and camel-derived VHH have 3 CDRs. On the other hand, a shark-derived variable domain of a new antigen receptor (VNAR) has 2 CDRs (page 18).
However, the claims encompass far more than the species disclosed in the specification. As noted above, the claims encompass a vast genus of antibodies described solely in terms of their function and/or a partial structure. The specification does not provide adequate written description to identify the broad genus of the claims because the specification does not disclose a correlation between the necessary structure of the antibody, and the claimed functions to be maintained (i.e. receptor tyrosine kinase agonist comprising a single domain antibody having a cell growth activity). Thus, the specification does not distinguish the claimed genus from others, except by function. Although the term “ single domain antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to its specific binding function; therefore, correlation is less likely for antibodies than for other molecules. Accordingly, the specification does not define any structural features commonly possessed by members of the genus because, while the description of an ability of a claimed antibody may generically describe that molecule’s function, it does not describe the molecule itself. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is; therefore it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of single domain antibodies, is highly variable (i.e. each different single domain antibody capable of having cell growth activity would necessarily have a unique sequence of amino acids; see MPEP 2434), the functional characteristic of binding to something specific, is insufficient to describe the genus. Further, given the highly diverse nature of antibodies, particularly in CDRs, even one of skill in the art cannot envision the structure of an antibody by only knowing its binding characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of antibodies and variants thereof claimed only by a functional characteristic(s) and/or partial structure.
Additionally, the specification fails to disclose a representative number of species. As noted above, some claim embodiments do not recite any structure and other embodiments state that the single antibody comprises three CDR sequences or heavy chain variable region. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. Although the specification discloses exemplary species, these species are not representative of the genus. 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. Furthermore, there is no description of an single antibody comprising fewer than all three CDRs or variant having a particular sequence identity to the given heavy chain CDR sequences that have the recited functions, and thus, the specification does not describe species that reflect the variation within 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 gen[us]; emphasis added. "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).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claims, claimed only by a partial structure and functional characteristics 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 antibodies 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 antibodies claimed only by a partial structure and functional characteristics.
In Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017), relying upon Ariad Pharms., Inc. v. Eli Lily & Co., 94 USPQ2d 1161 (Fed Cir. 2010), it is noted that to show invention, a patentee must convey in its disclosure that is “had possession of the claimed subject matter as of the filing date. Demonstrating possession “requires a precise definition” of the invention. To provide this precise definition” for a claim to a genus, 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 at page 1358). Also, it is not enough for the specification to show how to make and use the invention, i.e., to enable it (see Amgen at page 1361). 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). Most significant to the present case, the Court held that "knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies" (Amgen at 1361). The idea that written description of an antibody can be satisfied by the disclosure of a newly-characterized antigen “flouts basic legal principles of the written description requirement” as it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen... And Congress has not created a special written description requirement for antibodies” (Amgen at page 1362).
Abbvie v. Centocor (Fed. Cir. 2014) is also relevant to the instant claims. In Abbvie, the Court held that a disclosure of many different antibodies was not enough to support the genus of all neutralizing antibodies because the disclosed antibodies were very closely related to each other in structure and were not representative of the full diversity of the genus. The Court further noted that functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support especially in technology fields that are highly unpredictable where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus.
The instant case has many similarities to AbbVie above. First, the claims clearly attempt to define the genus of receptor tyrosine kinase agonist comprising a single domain antibody by the function of having a cell growth activity. As noted by AbbVie above, functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description. Second, there is no information in the specification based upon which one of skill in the art would conclude that the disclosed species for which applicant has identified as having the recited functions would be representative of the entire genus. The specification discloses no structure to correlate with the function. Therefore, 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 antibodies, 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.
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.
The state of the art regarding receptor tyrosine kinase agonist comprising a single domain antibody having cell growth activity is discussed by Harmsen, et al (Harmsen MM, De Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol. 2007 Nov;77(1):13-22. doi: 10.1007/s00253-007-1142-2. Epub 2007 Aug 18. PMID: 17704915; PMCID: PMC2039825). Harmsen teaches the single domain antibody fragment different by only a few amino acids are obtained and behave very differently and that she specific amino acid change responsible for a given functional difference is difficult to predict. Harmsen further teaches the antigen-binding CDRs of these antibody vary substantially among clones.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. In the instant case, the claimed antibody is a single domain antibody that requires three heavy CDRs. Paul (Fundamental Immunology, 3rd Edition, Raven Press, New York, Chapter 8, pages 292-295, 1993) teaches that the amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences, which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (See pages 293-295). While some publications acknowledge that CDR3 is important for antigen binding, the conformations of other CDRs as well as the framework are equally important in antigen binding. For example, MacCallum et al. (Journal of Molecular Biology, 262:732-745, 1996) analyzed antigen-contacting residues and combining site shape of various antibodies and state that although CDR3 of the heavy chain and light chain dominate, a number of residues outside of the standard CDR definitions make antigen contacts (See page 733). MacCallum et al. teach that antigens tend to bind to the antibody residues located at the center of the combining site where the six CDRs meet (See abstract and page 742) and less central CDR residues are only contacted by large antigens (See page 733 and 735). MacCallum et al. further teach that non-contacting residues are important in defining "canonical" backbone conformations.
The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is further underscored by Casset et al. (Biochemical and Biophysical Research Communications, 307:198-205, 2003), which discuss the importance of multiple CDRs in antigen contact. Casset et al. teach that all antibodies have six CDR residues, all of which are more or less involved in antigen recognition (See page 199). Casset et al. teach that peptide mimetics of antibody combining sites have previously only targeted CDR H3, since this CDR is typically at the center of most, if not all, antigen interactions; however this strategy is flawed since other CDRs play an important role in the recognition of antigen (See page 199). Casset et al. construct a peptide mimetic of an anti-CD4 monoclonal antibody, containing antigen contact residues from five CDR regions, except L2 and additionally using a framework residue located just before the H3 and show that the peptide has high binding to CD4, thus signifying the contribution of multiple CDRs, and not a single CDR, in antigen recognition (See page 202 and Figure 4).
Vajdos et al. (Journal of Molecular Biology, 2002 Jul 5;320(2):415-28) additionally teaches that, “ ... Even within the Fv, antigen binding is primarily mediated by the complementarity determining regions (CDRs), six hypervariable loops (three each in the heavy and light chains) which together present a large contiguous surface for potential antigen binding. Aside from the CDRs, the Fv also contains more highly conserved framework segments which connect the CDRs and are mainly involved in supporting the CDR loop conformations, although in some cases, framework residues also contact antigen. As an important step to understanding how a particular antibody functions, it would be very useful to assess the contributions of each CDR side-chain to antigen binding, and in so doing, to produce a functional map of the antigen-binding site.
Further, Sela-Culang et al. 2013 (The structural basis of antibody-antigen recognition; Frontiers in Immunology 4(302):1-13) teach the hypervariable loops within the variable domains of antibody polypeptides are widely assumed to be responsible for antigen recognition while the constant domains are believed to mediate effector activation, but that recent analysis indicates that their clear functional separation between the two regions is an over-simplification (see abstract). Sela-Culang et al. teach some residues within the CDRs may not participate in antigen binding and some residues outside the CDRs (e.g. in framework regions and in the constant domains) often contribute critically to the integration with the antigen (see abstract). Sela-Culang et al. teach understanding the role of each structural element is essential for successful engineering of binding polypeptides (e.g. page 2, left column). Sela-Culang et al. teach almost all of the residues predicted to be part of an epitope may be considered as correct predictors as they will bind to some antibodies but also are false predictors as they don’t bind to the others and accordingly that predicting that a residue is not in an epitope may be either a true negative or a false negative depending on the anybody considered (page 2, right column). Sela-Culang et al. teach each CDR has its own unique amino-acid composition different from the composition of the other CDRs and that each CDR has a unique set of contact preferences favoring certain amino acids over others (page 5-6, bridging). Sela-Culang et al. teach the combined action of all six CDRs is the evolutionary response of the immune system that enables the antibody polypeptide to recognize virtually any surface patch on the antigen (page 6). Thus, the state of the art recognized that it is highly unpredictable that an antibody comprising one or even all six CDRs, wherein the CDRs are not in their proper order or in the context of framework sequences which maintain their required conformation would have the requisite antigen binding function. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the antibody 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 antibodies defined solely in terms of their function and/or comprising fewer than three CDRs 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 antibodies.
Consequently, the vast genus of antibodies encompassed by the claims do not meet the written description provision of 35 USC 112, first paragraph. The species specifically disclosed are not representative of the genus because the genus is highly variant. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115).
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.
9. Claim 1-4, 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez Pajuelo, et al. (US 2011/0282033 A1, published 17 November 2021) in view of Koledova, et al. (Koledova Z, Sumbal J, Rabata A, de La Bourdonnaye G, Chaloupkova R, Hrdlickova B, Damborsky J and Stepankova V (2019) Fibroblast Growth Factor 2 Protein Stability Provides Decreased Dependence on Heparin for Induction of FGFR Signaling and Alters ERK Signaling Dynamics. Front. Cell Dev. Biol. 7:331. doi: 10.3389/fcell.2019.00331).
The instant claims are drawn to a receptor tyrosine kinase agonist comprising a single-domain antibody having a cell growth activity, wherein the receptor tyrosine kinase agonist is at least one receptor tyrosine kinase agonist selected from the group consisting of a human fibroblast growth factor receptor 1 (FGFR1), a human fibroblast growth factor receptor 2 (FGFR2), a human fibroblast growth factor receptor 3 (FGFR3), and a human fibroblast growth factor receptor 4 (FGFR4).ow do
Gonzalez teaches single-domain antibody amino acid sequences and polypeptides directed against growth factor receptors, including the fibroblast growth factor family such as FGFR1, FGFR2, FGFR3 and FGFR4. Gonzalez teaches that such polypeptides can be used as an agonist of growth factor receptors (paragraph 18) and can bind to growth factor receptors and thus activate, trigger, upregulate or stimulate growth factor receptors and/or the biological pathways, signaling, mechanisms, responses and/or effects in which they are involved (paragraph 20 and 548). Gonzalez further teaches that the multivalent single domain antibody construct promotes dimerization of the receptors, thereby activating receptor signaling (paragraph 557), consistent with the activation of these receptor by dimerization and autophosphorylation (paragraph 24) and acknowledges that agonism of FGFR1 is known in the art (paragraph 28). Thus, Gonzalez teaches a single domain antibody that is an agonist of FGFR1-FGFR4. Gonzalez further teaches multivalent single domain antibody constructs in which two or more single domain antibody amino acid sequences are joined by a linker (paragraph 557-559) and teach the single domain antibody sequences in its multivalent constructs are joined by a linker, including peptide linkers (paragraph 557), thus reciting the limitations on instant claim 3, 4, 13 and 14.
Gonzalez does not explicitly teach the phrase “cell growth activity” in instant claim 1 or the EC50 value in instant claim 2
However, Koledova teaches activation of FGFR1-3 by an FGFR agonist produces cell proliferation (cell growth activity) (introduction section). Koledova further teach the wild-type FGF2 induced FGFR-mediated proliferation with an EC50 of 0.098 nM (table 1) which converts to 0.001 µg/mL for an FGF2 protein which is below the recited ceiling of 10 µg/ml. One of ordinary skill in the art would modify the teachings of Gonzalez, et al. to include provide it as an agonist having cell growth activity and also the quantitative value of EC50, because Koledova teaches that agonism of FGFR1-3 produce cell growth response which is a functional outcome of agonizing the FGF receptor. The use of a known technique to improve similar products in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
10. Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez Pajuelo, et al. and Koledova, et al as applied to claims 1-4, 13 and 14 and in further view of Harmsen, et al. (Harmsen MM, De Haard HJ. Properties, production, and applications of camelid single-domain antibody fragments. Appl Microbiol Biotechnol. 2007 Nov;77(1):13-22. doi: 10.1007/s00253-007-1142-2. Epub 2007 Aug 18. PMID: 17704915; PMCID: PMC2039825.)
Instant claim 5 and 6 are drawn the denaturation temperature and dissociation constant of the tyrosine kinase agonist.
Gonzalez and Koledova do not teach denaturation temperature and disassociation constant of instant claim 5 and 6
However, Harmsen teaches that the camelid single domain antibody possess high thermal stability, remaining functional at 90°C and refolding efficiently after thermal or chemical denaturation (properties section, paragraph 6). It would have been obvious to one of ordinary skill in the art before the effective filing date that the camelid single domain antibody agonist of Gonzalez would possess a denaturation temperature of 65°C or higher, as Harmsen teaches such thermostability is characteristic of the single domain antibody scaffold. Thus, reciting the limitation of instant claim 5. Harmsen further teaches that single domain antibody affinities are comparable to those of conventional antibody fragments and that single domain antibody with affinity constant as low at 1 X 10^-10 (properties section, paragraph 7), which is within the recited range of taught by instant claim 6. It would have been obvious to one of ordinary skill in the art to provide the camelid single domain antibody FGFR agonist of Gonzalez with a KD of 5 x 10^-9 M or less, as Harmsen teaches those affinities are routinely achieved for the single domain antibody scaffold. Harmsen further teaches the most characteristic feature of camelid single domain antibody is the presence of amino acid substitution at 37, 44, 45 and 47 (Kabat numbering) amino acid positions.
11. Claims 8 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Gonzalez Pajuelo, et al. , Koledova, et al and, Harmsen, et al as applied to claims 1-6, 13 and 14 and in further view of Muyldermans, et al. (US 9156905 B2, issued 13 October 2015).
Instant claim 8 and 15 recite specific framework residues.
Gonzales, Koledova and Harmsen do not teach the specific amino acid residues.
However, Muyldermans teaches the specific residues at these positions. Muyldermans teaches in the single domain antibody, the residues Phe37 (or Tyr), Glu44, Arg45 (or Cys), and Gly47 (or Leu) (paragraph 11 and column 3). These residues fall within the groups recited in instant claim 8 and 15. The camelid single domain antibodies of Gonzalez inherently possess these hallmark FR2 residues at the recited Kabat positions. It would be obvious to one of ordinary skill in the art before the effective filing date that the single domain antibody of Gonzalez includes, at the recited position, residues falling within the recited groups, as taught by Harmsen and Muyldermans. The combination of familiar elements is likely to be obvious when it does no more than yield predictable results. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, A.).
12. Claims 9 -12 are rejected under 35 U.S.C 103 as being unpatentable over Gonzalez Pajuelo, et al, Koledova, et al, Harmsen, et al, and Muyldermans, et al. as applied to claims 1-6, 8 and 13-15 and in further view of Lotz, et al. (Lotz S, Goderie S, Tokas N, Hirsch SE, Ahmad F, et al. (2013) Sustained Levels of FGF2 Maintain Undifferentiated Stem Cell Cultures with Biweekly Feeding. PLOS ONE 8(2): e56289. https://doi.org/10.1371/journal.pone.0056289)
Instant claim 9-12 are drawn to a medium composition for cell culture, containing 0.1 ng/mL to 10 g/mL of a receptor tyrosine kinase agonist, wherein the receptor tyrosine kinase agonist includes a single-domain antibody having a cell growth activity, and is at least one selected from the group consisting of a human fibroblast growth factor receptor 1 (FGFR1), a human fibroblast growth factor receptor 2 (FGFR2), a human fibroblast growth factor receptor 3 (FGFR3), and a human fibroblast growth factor receptor 4 (FGFR4); the medium composition for cell culture according claim 9 to wherein a cell grown by the cell growth activity is at least one cell selected from the group consisting of a fibroblast, a mesenchymal stem cell, and an iPS cell; a composition for maintaining an undifferentiated state of a stem cell, the composition comprising the receptor tyrosine kinase agonist according to Claim 1 as an active ingredient; The composition for maintaining an undifferentiated state according to claim 11, wherein the stem cell is a mesenchymal stem cell or an iPS cell.
The teachings of Gonzalez Pajuelo, et al, Koledova, et al, Harmsen, et al, and Muyldermans, et al. are above.
Gonzalez Pajuelo, et al, Koledova, et al., Harmsen, et al, and Muyldermans, et al. do not teach instant claims 9-12.
However, Lotz, et al. teach a cell culture medium containing FGF2 which is an FGFR agonist that acts through FGF receptors and MAPK pathway, at a concentration of 10 ng/ml, which is within the recited range of instant claim 9, used to support undifferentiated stem cell growth (Result and method section). It would have obvious to one o ordination skill in the art to substitute the FGFR agonist single domain antibody of Gonzalez for the FGF2 of Lotz in Lotz’s medium. A skilled artisan would have motivation to do so as Lotz’s teaching of FGF2 is highly labile, decreasing by more than 50% within four hours at 37 C, which provides a more stable FGR agonist. The simple substitution of one known element for another is likely to be obvious when predictable results are achieved. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, B.).
Lotz further teaches culturing induced pluripotent stem cells in FGF2 containing medium, and the FGF2 improving their undifferentiated growth (paragraph 7 and figure 3). Thus, this recites the limitation of instant claim 10. Lotz teaches that FGF2, an FGFR agonist, is the active component that maintain stem cells in the undifferentiated state, sustained FGF2 levels increasing stem cell marker expressing and decreasing spontaneous differentiation (discussion section). Thus, this recites the limitation of instant claim 11. Lotz, et al. further teaches maintenance of iPS cells in the undifferentiated state by the FGFR agonist (results section, paragraph 2), thus, reciting the limitation of instant claim 12.
Conclusion
13. No claims are allowed.
14. 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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