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 .
Applicant’s election of group I, claims 1-13 and 18-19 in the reply filed on 1/23/26 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 14-17 and 20-21 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 1/23/26.
Claims 1-13 and 18-19 are under examination.
Claim Objections
Claims 5-9, 11-13, and 18-19 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits. Appropriate correction is required.
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 1-4 and 10 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
The instant claims are drawn to a cyclic peptide comprising an amino acid sequence having the structure of formula (I) (SEQ ID NO: 1) and variants thereof: X1X2X3FX4HDSGX5X6X7X8H.
This issue with regards to written description is that the claims encompass a genus of variants that have no correlation between their structure and function. Although the claims are inclusive the cyclic peptides having the amino acid sequence set forth in SEQ ID NO: 4, 5, and 7-14, the claims broadly encompass variants of SEQ ID NO: 1, 4, 5, and 7-14. Some claim embodiments encompass variant peptides having 85% sequence identity the sequences set forth in SEQ ID NOs: 1, 4, 5, and 7-14. The specification teaches that variant cyclic peptides have the same or similar function as their reference peptide, i.e., are functionally equivalent cyclic peptides, and adopt the hairpin structure of amyloid-beta. This would represent a large pool of variant polypeptides that must have similar functional activity. A variance of 15%, for example, in the amino acid sequence set forth in SEQ ID NO: 4 that is 14 amino acid residues in length translates into 2 amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 14 amino acid sequence. 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 85%. Applicants have not described which domain or portions of SEQ ID NOs: 1, 4, 5, and 7-14 that 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) are claimed only be their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences).
The second issue is the use of the term “an” when describing the cyclic peptide sequences, for example in claim 1 “a cyclic peptide comprising an amino acid sequence having the structure of formula I (SEQ ID NO:1)”.” It is also possible, given the language of the claim which includes "an amino acid sequence", that any two amino acids in sequence would suffice to meet the limitations of the claims. Because function of protein is dependent on the presence of each specific amino acid residue, and with the possibility of added or deleted amino acids, a wide variety of polypeptides, is encompassed by the instant claim. In addition, the phrase “an amino acid sequence” allows any fragment, including any two amino acids in sequence, to be encompassed in the instant claim. This would in theory encompass any possible peptide. These peptides have no correlation between their structure and function. It is recommended that Applicant amend the language of the claim to recite “having the amino acid sequence” in all places that “an amino acid sequence” appears to overcome this issue.
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 cyclic peptides having the amino acid sequences set forth in SEQ ID NO: 4, 5, and 7-14 and the required function, 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 sequences and encompass variants of the claimed sequences. 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 cyclic peptides having the amino acid sequences set forth in SEQ ID NO: 4, 5, and 7-14, the skilled artisan cannot envision the detailed chemical structure of the encompassed variant cyclic 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.
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) 1-4 and 10 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Cashman et al. (WO2017079831 A1, published May 18, 2017).
The instant claims are drawn to a cyclic peptide comprising an amino acid sequence having the structure of formula (I) (SEQ ID NO: 1) and variants thereof: X1X2X3FX4HDSGX5X6X7X8H. Cashman et al. teach backbone cyclic and/or side-chain cyclized peptides from the N-terminal region of Aß protein as neuroprotective immunogens (See example 3). Cashman et al. teach cyclo(CGHDSGG) (See paragraph 00430). It should be noted that the specification teaches that the term variant refers to cyclic peptides having the same function or similar as their reference peptide, i.e., are functionally equivalent peptide, and adopt the hairpin structure of amyloid-beta. In light of the definition of "variant", the limitation "cyclic peptide of formula I or variants thereof" is not limited to cyclic peptides having formula I, but encompasses peptides having differing structures, but the same or equivalent function. Thus, the cyclic peptides of Cashman et al. meet the limitation of variant cyclic peptides of formula I. Cashman et al. teach a pharmaceutical composition comprising the cyclic peptide and a pharmaceutically acceptable carrier (See paragraph 0075). Cashman et al. teach that the composition further comprises an adjuvant (See paragraph 00310-00312). Cashman et al. teach that the cyclic peptide is used for treating Alzheimer’s disease (See paragraph 0071). Thus, Cashman et al. anticipate the claims.
Claim Status
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa L. Ford can be reached at (571)272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SANDRA CARTER/ Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
Prosecution Insights