DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The preliminary amendment filed 5/1/24 is acknowledged. Claims 10-15 have been amended. Claims 1-15 are pending and under examination.
Claim Interpretation
It should be noted that the claim language “an amino acid sequence of SEQ ID NO: 1” encompasses the full-length peptide sequence or any portion of SEQ ID NO: 1. This language encompasses any sequence of two or more amino acids fully contained within SEQ ID NO:1, and is thus, anticipated by any dipeptide or larger peptide.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the 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 peptide comprising an amino acid sequence of SEQ ID NO: 1.
The issue with regards to the written description provision of 112(a) is the use of the term “an” when describing the peptide sequence, for example in claim 1 “a peptide comprising an amino acid sequence of SEQ ID NO:1”.” It is 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 peptides, 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 “comprising the amino acid sequence” in all places that “an amino acid sequence” appears to overcome this issue.
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 peptide having the amino acid sequence set forth in SEQ ID NO: 1 and the required function(s) (i.e., cartilage regenerative activity, anti-inflammatory activity, osteoporosis inhibitory activity, promote differentiation of stem cells into chondrocytes, increase synthesis of ECM, inhibits expression of inflammatory cytokines, inhibits differentiation of macrophages into osteoclast), 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 amino acid sequence and encompass fragments of the claimed sequence. 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 few species have been described and this is not considered to be representative of the breadth of the genus.
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.)
With the exception of the peptide having the amino acid sequence set forth in SEQ ID NO: 1, the skilled artisan cannot envision the detailed chemical structure of the encompassed peptides, 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 survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the amino acid sequences per se and thereby does not provide adequate written description support for which structural features of any given polypeptide would predictably retain their functional activities.
Applicant is reminded that generally, in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus (Enzo Biochem, Inc. v. Gen- Probe Inc., 323 F.3d 956 (Fed. Cir. 2002); Noelle v. Lederman, 355 F.3d 1343 (Fed. Cir. 2004); Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). A patentee must disclose “a representative number of species within the scope of the genus of structural features common to the members of the genus so that one of skill in the art can visualize or recognize the member of the genus” (see Amgen Inc. v. Sanofi, 124 USPQ2d 1354 (Fed. Cir. 2017) at page 1358). An adequate written description must contain enough information about the actual makeup of the claimed products — “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2dat1966.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, ‘does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the “written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed. Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Claims 1-15 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 peptide comprising the amino acid sequence set forth in SEQ ID NO: 1, does not reasonably provide enablement for a peptide comprising an amino acid sequence of SEQ ID NO: 1. 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) The nature of the invention, (6) Breadth of the claims and (8) Undue experimentation
The nature of the invention is a peptide comprising an amino acid sequence of SEQ ID NO:1. It is 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 peptides, 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. 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 peptide comprising an amino acid sequence of SEQ ID NO: 1, 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 claims also broadly encompass preventing any inflammatory disease and osteoporosis. The specification supports the examiner’s position that the claims are broad. teaches the inflammatory disease may refer to a pathological condition that causes inflammation caused by neutrophil chemotaxis among white blood cells, and may include, but is not limited to, any disease caused by an inflammatory response or accompanied by an inflammatory response. The specification teaches that examples of the inflammatory disease include, but are not limited to, rhinitis, bronchitis, periodontitis, pancreatitis, gastritis, gastric ulcer, an inflammatory skin disease, atopic dermatitis, encephalitis, sepsis, inflammatory enteritis, a chronic obstructive pulmonary disease, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, inflammatory osteolysis, a chronic inflammatory disease caused by a chronic virus or bacterial infection, colitis, an inflammatory bowel disease, type 1 diabetes, rheumatoid arthritis, reactive arthritis, osteoarthritis, psoriasis, scleroderma, osteoporosis, atherosclerosis, myocarditis, endocarditis, pericarditis, cystic fibrosis, Hashimoto's thyroiditis, Graves' disease, leprosy, syphilis, Lyme disease, borreliosis, neurological borrelia, tuberculosis, sarcoidosis, lupus, discoid lupus, chilblain lupus, lupus nephritis, systemic lupus erythematosus, macular degeneration, uveitis, irritable bowel syndrome, Crohn's disease, Sjogren's syndrome, fibromyalgia, chronic fatigue syndrome, chronic fatigue immune dysfunction syndrome, myalgic encephalomyelitis, amyotrophic lateral sclerosis, Parkinson's disease, and multiple sclerosis.
Thus, given the broadest reasonable interpretation, the claims encompass using any number of peptide fragments for treating or preventing osteoporosis and any number of inflammatory diseases. The recitation of the claims, as written, amounts to undue experimentation. That is, it would be undue experimentation to determine if osteoporosis and any number of inflammatory diseases are amenable to treatment with the claimed peptide fragments.
(2) The state of the prior art and (4) The predictability or unpredictability of the art
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 survivins’ apoptotic function from anti-apoptotic to proapoptotic and changes in its subcellular localization (See page 1287-1289). Moreover, Defeo-Jones et al. (Molecular and Cellular Biology, Sept. 1989, p. 4083-4086) teach that the conservative substitution of lysine for arginine at position 42 completely eliminated biological activity (See abstract and pages 4084-4085). These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein.
Additionally, Bork (Genome Research, 2000; 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p. 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p. 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p. 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p. 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p. 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p. 400, paragraph bridging cols 1 and 2).
Given not only the teachings of Punta et al., Whisstock et al., Song et al., Burgess et al., and Defeo-Jones et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed proteins having the required function(s) could not be predicted based on sequence identity. Clearly, it could not be predicted that a polypeptide or a variant that shares only partial homology with a disclosed protein or that is a fragment of a protein will function in a given manner. Therefore, the state of the art supports that even the skilled artisan requires guidance on the critical structures of the amino acid sequences 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.
While the state of the art is relatively high with regard to the treatment of specific inflammatory disorder types, the state of the art with regard to broadly treating all inflammatory disorders is underdeveloped. In particular, there is no known agent that is effective against all inflammatory disorders. The inflammatory disease art involves a very high level of unpredictability. While the state of the art is relatively high with regard to the treatment of specific disorders with specific agents, it has long been underdeveloped with regard to the treatment of all inflammatory diseases. The lack of significant guidance from the present specification or prior art with regard to the actual treatment of all inflammatory diseases in a subject, with the claimed genus of peptides makes practicing the claimed invention unpredictable.
Predicting whether or not an agent will be able to treat a particular disease is fraught with obstacles, even if the patient population has a well-understood disease. As taught by Ma (Modern Drug Discovery 2004, 7(6)), any results from in vitro screening often poorly correlate with in vivo results because the complicated physiological environment is absent in the in vitro system (see page 30, left column).
In addition, predicting the success of a treatment for inflammatory disease presents challenges beyond initial screening. For example, regarding autoimmune disease, according to Steinman et al (Nat Med. 2012 Jan 6;18(1):59-65), there are no approved clinical tests that are effective at predicting the therapeutic success or toxicity of treatments for autoimmune diseases (see page 59). Further Steinman et al teach that a single therapeutic strategy is probably not suitable for all autoimmune diseases or even for individual subsets of patients within one diagnostic category, as there may be heterogeneous biology underlying some of these clinical entities (see page 61). Steinman et al give the example of biologics targeting TNF and its receptors, which are effective in rheumatoid arthritis, Crohn's disease and psoriasis, but which cause marked worsening of disease in multiple sclerosis (see page 60). Blumberg et al (Nat Med.; 18(1): 35–41) teach that one of the greatest problems in translating therapies into clinical practice in autoimmunity are the numerous failures that have been the results of clinical trials. Despite the rapid progress that has been made in understanding the immune system, most of the underlying data has come from animal models, which necessarily only partially represent what is observed in humans. To compound this limitation, there exists no standardized definition of the normal human immune system, no comprehensive understanding of how this normal system is altered in autoimmune diseases and no understanding of the relationship between these immunophenotypic characteristics and either the genetic composition of the host or the environmental stimuli that either promote or protect from the development of autoimmunity (see pages 1-3). It is important to remember that the claims are even broader than the field of autoimmune disorders, and encompass any known inflammatory disease. Given the extremely broad nature of the encompassed diseases, which have variable etiology and pathology, and the teachings of Steinman and Blumberg, one of skill in the art would not be able to predict the effectiveness of the encompassed peptides in each of the claimed inflammatory diseases.
(5) The amount of direction or guidance provided by the invention; (7) The existence of working examples
The working examples teach the peptide of SEQ ID NO: 1 promotes ECM production, as measured by increase in the formation of glycosaminoglycan, in chondrocytes. The working examples teach that treatment of human-derived chondrocytes with the peptide of SEQ ID NO:1 increased mRNA expression of collagen type II, aggrecan, and proteoglycan core protein, which are ECM components. The working examples teach that the peptide of SEQ ID NO: 1 promoted the formation of glycosaminoglycan in 3D culture of chondrocytes. The working examples teaches that the peptide of SEQ ID NO: 1 promoted the chondrogenic differentiation of the adipose-derived mesenchymal stem cells and the production of glycosaminoglycan. The working examples teach the peptide of SEQ ID NO: 1 increased production of SOX9 protein in adipose-derived mesenchymal stem cells. The working examples teach the peptide of SEQ ID NO: 1 promoted the expression of COMP, COL 11A, PCP, and ACAN genes associated with ECM production in the adipose-derived mesenchymal stem cells. The working examples teach the peptide of SEQ ID NO: 1 inhibited the expression of inflammatory cytokine genes induced by the treatment of inflammatory cytokines in mouse macrophages. The working examples teach the peptide of SEQ ID NO: 1 inhibited the increase in inflammatory proteins caused by the treatment of inflammatory cytokines in mouse macrophages, and had an inhibitory effect on the inflammatory response. The working examples teach peptide of SEQ ID NO: 1 inhibited the differentiation into osteoclasts induced by RANKL in mouse macrophage. The working examples teach the peptide of SEQ ID NO: 1 inhibited the activity of TRAP, which is a marker of osteoclasts, in mouse macrophages in a concentration-dependent manner. The working examples teach the peptide of SEQ ID NO: 1 inhibited the production of NFAT protein, which is a main transcription factor in the differentiation process of adipose-derived mesenchymal stem cells into osteoclasts. The working examples teach the peptide of SEQ ID NO: 1 of the present invention inhibited the formation of actin rings, which are essential for differentiation of mouse macrophages into osteoclasts.
(6) Breadth of the claims
Applicant is reminded that carrying out the recitations/limitations in a claim should not be a fishing expedition for a person of ordinary skill in the art. The grant of a patent is premised on this fundamental bargained-for exchange. The inventor must provide a full, complete, and enabling description of the invention and, in exchange, the government provides the inventor with the right to exclude others from practicing the invention. See LizardTech, Inc., v. Earth Res. Mapping, Inc., 424 F-3d 1336,1344 (Fed. Cir. 2005) (describing enablement as an essential part of the patent bargain); in Liebel-Flarsheim Co., v. Medrad., Inc, (Liebel IT) 481 F.3d 1371 (Fed. Cir. 2007) (holding that the claims must enabled the full scope of the broadest claim, even if one or more embodiments are specifically enabled) (at p. 14, last paragraph to page 15, first paragraph of CAFC slip op. 06-1156, 22 March 2007); and AKSteel Corp v. Sollac and Ugine, 344 F.3d 1234, 1343-44 (Fed. Cir. 2003). Moreover, the CAFC has held that claims broad enough to encompass significant nonenabled subject matter will be found nonenabled (Sitrick v. Dreamworks, LLC, 516 F.3d 993 (Fed. Cir. 2008). The holding in Sitrick is a restatement of the precedential CCPA holding in In re Cook and Merigold, 169 USPQ 298 (CCPA 1971) (supra).
The difference in scope between what is claimed and what is taught in the specification and prior art regarding the claimed peptides and pharmaceutical use, illuminate the fact that the instant claims are a single means claims. A single means claim (i.e. wherein a means recitation does not appear in combination with another recited element of means), is subject to an undue breadth rejection under 35 U.S.C. 112(a). In re Hyatt, 708 F.2d 712, 714-715, 218 USPQ 195,197 (Fed. Cir. 1983) (A single means claim which covered every conceivable means for achieving the stated purpose was held nonenabling for the scope of the claim because the specification disclosed at most only those means known to the inventor.). When claims depend on a recited property, a fact situation comparable to Hyatt is possible, where the claim covers every conceivable structure (means) for achieving the stated property (result) while the specification discloses at most only those known to the inventor. See MPEP 2164.08(a).
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 peptide and fragments thereof for treating and preventing osteoporosis and all inflammatory diseases, 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 peptide of SEQ ID NO: 1 for treating and preventing osteoporosis and all inflammatory diseases in a manner reasonable in correlation with the scope of the claims. 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 treating and preventing osteoporosis and all inflammatory diseases with the claimed peptides. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970). Applicant is reminded that specification does not disclose any fragment of the peptide of SEQ ID NO: 1 (i.e., an amino acid sequence of SEQ ID NO: 1), nor does the specification demonstrate treating or preventing osteoporosis and any inflammatory disease. Without such guidance, determining which disease can be treated and prevented with the claimed peptides 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 Exparte Forman, 230 U.S.P.Q. 546(Bd. Pat=. App & int. 1986).
Due to the extreme breadth of the claims, as written, the lack of guidance in the prior art, and the lack of guidance in the specification, one of ordinary skill in the art would have to engage in undue experimentation to make and use the invention of the claims, as written. In view of all of the above, the claimed invention does not satisfy the requirements of 35 U.S.C. 112 first paragraph.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-15 is/are rejected under 35 U.S.C. 102(a)(1a) and 102(a)(2) as being anticipated by Arap et al. (WO02/20822 A2, published March 14, 2002).
The instant claims are drawn to a peptide comprising an amino acid sequence of SEQ ID NO: 1.
Arap et al. teach a peptide comprising the sequence CDWGLWWLC (SEQ ID NO: 161), which is a peptide comprising an amino acid sequence of SEQ ID NO: 1 (See page 66). As noted above, the claim language “an amino acid” encompasses the full-length peptide sequence, as well as any dipeptide or larger peptide contained within the peptide sequence of SEQ ID NO:1.
Regarding the limitations “wherein the peptide has one or more physiological activities selected from the group consisting of cartilage regenerative activity, anti- inflammatory activity, and osteoporosis inhibitory activity”, “wherein the peptide promotes differentiation of stem cells into chondrocytes”, “wherein the stem cells are one or more selected from the group consisting of cord blood- derived stem cells, peripheral blood-derived stem cells, bone marrow-derived stem cells, and mesenchymal stem cells”, “wherein the peptide increases synthesis of an extracellular matrix (ECM) in chondrocytes”, “wherein the peptide increases expression of one or more genes selected from the group consisting of collagen type II (COL2A1), aggrecan (ACAN), and proteoglycan core protein (PCP) in chondrocytes”, “wherein the peptide inhibits expression of inflammatory cytokine”, “wherein the inflammatory cytokines are one or more selected from the group consisting of TNFα, IL-1 COX2, IL-6, IL-17, and IFNγ”, “wherein the peptide inhibits differentiation of macrophages into osteoclasts”, the aforementioned limitations recite properties of the claimed peptide. Since the prior art teaches the structure required by the claim, the prior art structure would inherently possess the claimed properties. "Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty.") See MPEP 2112
Regarding claims 10-15, the limitations “for generating cartilage”, “for preventing or treating an inflammatory disease”, “for preventing or treating osteoporosis”, “for preventing or ameliorating an inflammatory disease”, and “for preventing or ameliorating osteoporosis” recite the intended use of the peptide. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In the instant case, the prior art teaches a peptide having the claimed structure, and therefore, the peptide would be capable of the intended use recited in the instant claims. Thus, Arap et al. anticipate the claims.
Query Match 94.7%; Score 71; Length 9;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 2 CDWGLWWLC 10
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Db 1 CDWGLWWLC 9
Conclusion
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/SANDRA CARTER/ Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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