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 amendments filed 04/04/2025 are acknowledged. Claims 1-9 are amended. Claims 10-15 are cancelled. Claims 1-9 are pending and under examination.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted 06/28/2024, 03/10/2026, and 07/09/2026 and the references cited therein have been considered, unless indicated otherwise.
Specification
4. The use of the term “Bio Optics” and “Alcon” (page 29), 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 specifications for other trademarks and 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.
5. Claims 1-9 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particular point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 1 recited “A method of treating or suppressing dry eye disease in a subject.” The term “suppressing” renders the claim indefinite. The specification does not define “suppressing”, nor does it provide any standard by which the requisite degree or endpoint may be ascertained. It is unclear whether “suppressing” requires prevention of onset in a subject not yet manifesting dry eye disease, arrest of progressing, reduction in severity, or reduction of one or more particular signs or symptoms. Because “treating” and “suppressing” are recited in the alternative, the claim implies that “suppressing” possesses a scope distinct from treating, yet neither the claim nor the specification identifies what that distinction is. It is further noted that Applicant amended claim 1 to remove “preventing” while retaining suppressing”, leaving unresolved whether prophylactic scope has been relinquished or retained. One of ordinary skill in the art would not be reasonably apprised of the scope of the claimed method. Claims 2-8 are rejected as depending from claim 1.
6. Claim 5 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particular point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 5 recites that the pharmaceutical composition “reduces expression of inflammatory factors of corneal epithelial cell”. The limitation is indefinite for two reasons. The claim recites a relative reduction with identifying any baseline or comparator. It is unclear whether expression is reduced relative to an untreated cell, relative to the same cell prior to administration, relative to a cell treated with a control composition, or relative to some other reference. Second, the term “inflammatory factors” is not defined with the clarity required to establish the metes and bounds of the claim. The specification teaches inflammatory factor may be interleukins, CCL/CXCL family, Chitinase 3-like 1, pNFkB, or the like (page 9). This does not constitute a definition set worth with reasonable clarity. See MPEP 2111.01.
7. Claim 6 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particular point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 6 recites that the pharmaceutical composition “increases an expression level of mucin”. The term “mucin” denotes a family of proteins. The ocular surface expresses both membrane associated mucin and secreted mucins, which are produced by different cell population and are regulated differently. It is therefore unclear whether the claim requires an increase in a particular mucin, in any single mucin, or in total mucin expression.
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 “80% sequence identity” and the other issue is regarding lack of protein structure in claim 1.
8. First, claim 2 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. 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 the method of claim 1, wherein the protein HAPLN1 has a sequence identity of 80% or more to an amino acid sequence of SEQ ID NO: 1
The specification teaches according to an embodiment of the present disclosure, the protein may have a sequence identity of 80 % or more to an amino acid sequence of SEQ ID NO: 1 (page 4).
The claims encompass a genus of HAPLN1 protein that are not adequately described. Although the claims are inclusive of the HAPLN1 protein comprising the amino acid sequence of SEQ ID NO: 1, the claims also broadly encompass chimeric molecule complexes comprising variants of SEQ ID NO: 1 that are at least 80% identical to the full-length amino acid sequence. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 20%, for example, in the polypeptide set forth in SEQ ID NO: 1 that is 354 amino acids in length translates into 70 residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 354 residue amino acid polypeptide. There is no limit in the claims, as written, that the variance be contiguous. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made and still maintain a variance of 80%. Applicants have not described which domain or portions of SEQ ID NO: 1 are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of polypeptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants and fragments) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
Accordingly, the specification does not define any structural features commonly possessed by the members of the genus, because, while the description of an ability of the claimed protein may generically describe the protein’s function, it does not describe the protein itself. A definition by function does not suffice to define the genu because it is only an indication of what the protein does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves the result. In addition, because the genus of chimeric molecule complexes is highly variable (i.e., each complex would necessarily have a unique structure, See MPEP 2434), the generic description of the heterodimer is insufficient to describe the genus, Further, given the highly diverse nature of proteins, even one of skill in the art cannot envision the structure of the chimeric molecule complex only by knowing its functional characteristics. Thus, the specification does not provide substantive evidence for possession of this large and variable genus, encompassing a potentially massive number of chimeric molecule complexes claimed only by a functional characteristic and/or partial structure.
A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not sufficient identifying characteristics for written description purposes, even when accompanied by a method of obtaining the agent. The specification does not adequately describe the correlation between the chemical structure and function of the genus, such as structural domains or motifs that are essential and distinguish members of the genus from those excluded. Thus, the genus of antibodies has no correlation between their structure and function.
Furthermore, Applicants have not shown possession of a representative number of species that have the claimed function(s). The claims generically recite HAPLN1 protein. While the specification clearly sets forth a correlation between the HAPLN1 protein comprising SEQ ID NO: 1, and the functions of treating dry eye disease, 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 HAPLN1 comprising SEQ ID NO: and broadly encompass HAPLN1 protein comprising variants and fragments of SEQ ID NO: 1. Thus, the genus has substantial variation because of the numerous alternatives and combinations permitted. There is no description of the structure common to the members of the genus such that one of skill in the art can visualize or recognize the members of the genus. Therefore, only a single species has been described and this is not considered to be representative of the breadth of the genus.
MPEP §2163 states that for a generic claim, the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. If the genus has a substantial variance (as in the instant case), the disclosure must describe a sufficient variety of species to reflect the variation within that genus. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number to adequately describe a broad genus. The courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus (e.g., see In re Gostelli, 872, F. 2d at 1012, 10 USPQ2d at 1618).
Further, the disclosure of only one or two species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the genu[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when… the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Accordingly, the specification also does not provide adequate written description to identify the broad genus of the claimed, claimed only be a function characteristic(s) and not structures per se, because inter alia, it does not describe a sufficient number and/or a sufficient variety of representative species to reflect the breadth and variation within the claimed genus. Consequently, based on the lack of information within the specification, there is evidence that a representative number and a representative variety of the numerous heterodimers had not yet been identified and thus, the specification represents little more than a wish for possession. Therefore, one of skill in the art would not conclude that Applicant was in possession of the broad and highly variable genus of heterodimers claimed only by a partial structure and functional characteristic(s).
Vas-Cath Inc. v. Mahurkar, 19 U5PQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.)The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
With the exception of a HAPLN1 protein comprising SEQ ID NO:1, 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.”Id.
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, 1-9 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. Claims 2-9 are included in this rejection because they depend on claim 1. 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 method of treating or suppressing dry eye disease in a subject, the method comprising administering a pharmaceutical composition comprising hyaluronan and proteoglycan link protein 1 (HAPLN1), or a gene encoding HAPLN1, as an active ingredient to the subject.
The specification teaches that HAPLN1 is disclosed among about 200 protein examples of the gene used. The specification teaches a use of hyaluronan and proteoglycan link protein 1 (HAPLN1) or a gene encoding HAPLN1 used to prepare a pharmaceutical composition for preventing or suppressing dry eye disease.
The claims lack written description because the claims recite generic and incompletely described HAPLN1 or a gene encoding HAPLN1. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed HAPLN1 without adequate descriptions of its component parts or overall makeup. The generically claimed HAPLN1 do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the HAPLN1 as recited in the claims, as written. For instance, without knowing the structure of the HAPLN1 one would not be able to adequately describe the claimed fusion polypeptide construct. The claims state that the HAPLN1 can treat or suppress dry eye disease; however, this definition provides no name for the encompassed protein or the specific structure of the protein having the recited function.. Thus, the claims identify HAPLN1 solely by their function and/or partial structure.
Accordingly, the specification does not define any structural features commonly possessed by members of the genus, because while the description of an ability of the claimed agent may generically describe the agent’s function, it does not describe the agent itself. A definition by function does not suffice to define the genus because it is only an indication of what the agent 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 agents is highly variable (i.e., each fusion polypeptide would necessarily have a unique structure; see MPEP 2434), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed agonists have no correlation between their structure and function and the specification fails to provide adequate written description to support the genus of fusion polypeptides encompassed by the claims.
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 described HAPLN1, and the claimed function(s), 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 HAPLN1 and encompass a vast genus of protein comprising any HAPLN1. 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. Given the vast number of agents that are encompassed by the claims, the disclosure of a few species is not sufficiently representative of the broad genus of proteins encompassed by the claims. 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 protein, 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 USPQ2dl961,1966 (1997); In re Gosteli, 872 F.2dl008,1012,10 USPQ2dl614, 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 survivin results in the conversion of surviving’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). 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. and Burgess 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.
Applicant has provided little or no descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of HAPLN1 or a gene encoding HAPLN1. Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of HAPLN1 to Applicant. Even if a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form a completely constructed HAPLN1 such that one would be able to distinguish it from the proteins of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of HAPLN1 as claimed.
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.
Enablement
9. Claims 1-9 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating dry eye disease in a subject, the method comprising administering a pharmaceutical composition comprising hyaluronan and proteoglycan link protein 1 (HAPLN1), or a gene encoding HAPLN1, as an active ingredient to the subject, does not reasonably provide enablement for suppressing dry eye disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability, 5) existence of working samples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
1) Nature of the invention and 6) Breadth of the claims
The nature of the invention is a method of treating or suppressing dry eye disease in a subject, the method comprising administering a pharmaceutical composition comprising hyaluronan and proteoglycan link protein 1 (HAPLN1), or a gene encoding HAPLN1, as an active ingredient to the subject.
Therefore, the nature of the invention is a chemical case, wherein there is natural unpredictability in performance of certain species or sub-combinations other than those specifically enumerated; See MPEP 2163. Accordingly, it is the Office’s position that undue experimentation would be required to make and use the claimed HAPLN1 for suppressing dry eye disease, with a reasonable expectation of success, because it would not be predictable from the disclosure of any particular species what other species may or may not work; See MPEP 2164.03.
The specification does not provide written description for suppressing dry eye disease. The specification demonstrates that the polypeptide having the amino acid sequence set forth in SEQ ID NO: 1 treats dry eye disease, as shown by decreased damaged goblet cells, decreased detached cells, decreased tear volume, and reduced CFS levels in animal models. However, the specification does not demonstrate that the polypeptide has the function of suppressing dry eye disease The term "suppress" is defined as to keep from occurring or happening; however, the specification does not show that the polypeptides keeps dry eye disease from occurring. It should be noted that in models of dry eye disease, disease is induced and then the individual polypeptides are administered. Suppressing would necessarily mean that an individual would be given the claimed polypeptide, and such administration would ensure that the patient did not develop dry eye disease. However, the polypeptide is never administered before the onset of disease to show that the polypeptides prevent the development of dry eye disease in the animal models. Thus, the models provide guidance regarding the use of the polypeptides to treat dry eye disease, but not for suppression of arthritis.
(5) The state of the prior art and (7) The predictability or unpredictability of the art
The state of the art regarding treatment of dry eye disease is discussed by Stapleton, et al (Fiona Stapleton, Monica Alves, Vatinee Y. Bunya, Isabelle Jalbert, Kaevalin Lekhanont, Florence Malet, Kyung-Sun Na, Debra Schaumberg, Miki Uchino, Jelle Vehof, Eloy Viso, Susan Vitale, Lyndon Jones, TFOS DEWS II Epidemiology Report, The Ocular Surface, Volume 15, Issue 3, 2017, Pages 334-365, ISSN 1542-0124, https://doi.org/10.1016/j.jtos.2017.05.003.
(https://www.sciencedirect.com/science/article/pii/S154201241730109X). Stapleton, et al. teach that the natural history of treating and untreated dry eye disease has been the subject of only limited study and remained an important area for further research. The study reported, recommendation regarding the implementation of well-designed studies to estimate the incidence of the disease and to establish the natural history of treated and untreated disease.
Craig, et al. (Jennifer P. Craig, Kelly K. Nichols, Esen K. Akpek, Barbara Caffery, Harminder S. Dua, Choun-Ki Joo, Zuguo Liu, J. Daniel Nelson, Jason J. Nichols, Kazuo Tsubota, Fiona Stapleton, TFOS DEWS II Definition and Classification Report, The Ocular Surface, Volume 15, Issue 3, 2017, Pages 276-283, ISSN 1542-0124, https://doi.org/10.1016/j.jtos.2017.05.008.
(https://www.sciencedirect.com/science/article/pii/S1542012417301192) declined to incorporate the descriptors “chronic” and “progressive” into the definition of dry eye disease, stating that there is currently insufficient evidence to support inclusion of these terms, and that additional research, including dry eye natural history studies, should be formed inform future refinements to the definitions. One of ordinary skill in the art would have had no baseline against which to determine whether administration of a composition to a subject not manifesting dry eye disease has prevented, delayed or otherwise suppressed the onset of the disease.
The art further establishes that no validates criterion existed by which subjects who would develop dry eye disease could be identified in advance of onset. The Epidemiology Report reports that risk factors were categorized as modifiable or non-modifiable, and as consistent, probable, or inconclusive, reflecting that a substantial proportion of identified risk factors had not established with consistency across studies. That report further determined that prevalence of dry eye disease ranged from 5 to 50%, and that the prevalence of signs was higher and more variable than of symptoms and that incidence was higher in women at 25, than in men, 17.3%, over a ten year period after adjusting for age.
The art further establishes that the presence of dry eye disease could not be determined by a single objective measure. Wolffsohn, et al. (James S. Wolffsohn, Reiko Arita, Robin Chalmers, Ali Djalilian, Murat Dogru, Kathy Dumbleton, Preeya K. Gupta, Paul Karpecki, Sihem Lazreg, Heiko Pult, Benjamin D. Sullivan, Alan Tomlinson, Louis Tong, Edoardo Villani, Kyung Chul Yoon, Lyndon Jones, Jennifer P. Craig, TFOS DEWS II Diagnostic Methodology report,
The Ocular Surface, Volume 15, Issue 3, 2017, Pages 539-574, ISSN 1542-0124, https://doi.org/10.1016/j.jtos.2017.05.001. (https://www.sciencedirect.com/science/article/pii/S1542012417301106) sets forth a compositive diagnostic protocol in which, prior to diagnosis, condition that can mimic dry disease are first excluded by triaging questions, after which symptoms screening with the DEQ-5 or SODI triggers the conduct of diagnostic tests of breakup time, osmolarity, OSS with fluorescein and lissamine green. No single test within the protocol is dispositive of the diagnosis. Where the presence of disease is established online by a compositive of assessment, none individually determinative, one of ordinary skill in the art could not reliably determine that disease had failed to occur in a given subject and therefore could not determine whether administration had suppressed the onset of dry eye disease.
In view of Craig, Stapleton, and Wolffsohn, the specification is not commensurate in scope with the claimed method of suppressing dry eye disease. It discloses no example in which the composition is administered to a subject prior to the onset of dry eye disease, no criteria by which subjects at risk of developing dry eye disease may be identified, no dosing regimen or duration directed to prophylactic use, and no measure or endpoint by which suppression of disease onset may be assessed. Practicing the claimed method to suppress the onset of dry eye disease would require one of ordinary skill in the art to design and conduct prevent studies of undetermined population, end and duration and such experimentation is undue.
(6) The amount of direction or guidance by the inventor; (7) The existence of working examples
The specification teaches that the polypeptide having the amino acid sequence set forth in SEQ ID NO: 1 treats dry eye disease, as shown by decreased damaged goblet cells, decreased detached cells, decreased tear volume, and reduced CFS levels in animal models
Applying the above test to the facts of record, it is determined that 1) no declaration under 37 C.F.R. 1.132 or other relevant evidence has been made of record establishing the amount of experimentation necessary, 2) insufficient direction or guidance is presented in the specification with respect to making and using the claimed polypeptide for preventing rheumatoid arthritis, 3) the relative skill of those in the art is commonly recognized as quite high (post-doctoral level). One of skill in the art would require guidance, in order to make or use the claimed polypeptide for treating rheumatoid arthritis. Without proper guidance, the experimentation to is undue.
The Applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including suppressing dry eye disease with the claimed HAPLN1. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, suppressing dry eye disease with the claimed HAPLN1 is unpredictable and the experimentation left those skilled in the art is unnecessarily and improperly, extensive and undue. See Amgen Inc v Chugai Pharmaceutical Co Ltd. 927 F 2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991) at 18 USPQ2d 1026-1027 and Ex parte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
In view of all of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention, and thus, the claimed invention does not satisfy the requirements of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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.
10. Claim 1 and 8-9 are rejected under 35 U.S.C. 103 as being unpatentable over Rhee, et al. (Rhee M, Mah F Inflammation in Dry Eye Disease Ophthalmology, 124, S14-S19)
in view of Mildwid, et al (WO 2011126833 A2).
It is noted prior to the rejection set forth that “treatment” in instant claim is defined in the specification as treating, curing, alleviating, relieving, modifying, ameliorating, or influencing symptoms of the disease or disorder.
The instant claims are drawn to a method of treating or suppressing dry eye disease in a subject, the method comprising administering a pharmaceutical composition comprising hyaluronan and proteoglycan link protein 1 (HAPLN1), or a gene encoding HAPLN12 as an active ingredient to the subject.
Rhee establishes that inflammation is established as the common etiopathogenic mechanism in dry eye disease and both a cause and effect of dry disease (introduction). Rhee further teaches dry eye disease is a heterogeneous disorder of the ocular surface in which the common denominator is inflammation; it is both a cause and effect of the disease (conclusion). Rhee further teaches challenges in the study and management of dry eye disease include need to advance diagnostic to match the pipeline of therapeutics.
Rhee does not teach HAPLN1 as a therapeutic for the inflammation caused by dry eye disease.
Mildwid teach administering HAPLN1 as an anti-inflammatory therapeutic. Mildwid further teach an HAPLN1 polypeptide is characterized in that, when it is administered to subjects with diseases with inflammatory diseases, one or more features of their inflammatory disease is attenuated (paragraph 51). Mildwid further teach the HAPLN1 therapeutics can be administered via ophthalmic, and parenterally (paragraph 108).
One of ordinary skill in the art would have motivated to treat the inflammation caused by dry eye disease taught by Rhee with the HAPLN1 therapeutic taught by Mildwid, as Rhee reports that challenges in treating inflammation in dry eye disease include management therapeutics, and Mildwid provides the solution to the inflammation caused by dry eye disease.
Additionally, a rationale to support a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395 (2007) (see MPEP §§ 2143, A. and 2143.02).
Conclusion
11. No claims are allowed.
12. 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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