The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment filed on 12-18-2025 is acknowledged. Claims 1, 4, 11 and 14 have been amended. Claims 2 and 3 have been canceled. Claims 1-4-6 and 8-19 are pending. Claims 6, 8-10 and 12-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 4-5 and 11 are currently under examination.
Claim Objections
The objection to claim 11 for reciting claim language drawn to non-elected inventions is withdrawn in light of the amendment thereto.
Claim Rejections Withdrawn
The provisional rejection of claims 1-5 and 11 on the ground of nonstatutory double patenting as being unpatentable over claim 1-2, 8-11, 15-18 and 22 of copending Application No. 17/997,455 (reference application) is withdrawn in light of the Terminal Disclosure filed on 12-18-2025.
Claim Rejections Maintained
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.
The rejection of claims 1, 4-5 and 11 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 is maintained for reasons of record. The cancellation of claims 2 and 3 has rendered the rejection of those claims moot. 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.
Applicant argues:
1. The amended claims now meets the written description requirement.
2. The technical feature of the present invention is that in SEQ ID NO: 31, the amino acid corresponding to the 12th position is substituted with tyrosine (Y), alanine (A), serine (S), or arginine (R) or the amino acid corresponding to the 116th position is substituted with aspartate
(D), serine (S), threonine (T), or glycine (G), thereby increasing the enzyme activity of serine protease. That is, the positions of the amino acids to be substituted in SEQ ID NO: 31, that is, the 12th and 116th positions, and the amino acids after substitution are important technical features.
3. Examples 1 to 3 specifically confirmed that serine protease variants in which the amino acid corresponding to the 12th position of SEQ ID NO: 31 is substituted with tyrosine (Y), alanine (A), serine (S) or arginine (R), or the amino acid corresponding to the 116th position is substituted with aspartate (D), serine (S), threonine (T), or glycine (G), exhibit superior enzyme activity compared to the wild-type (see Tables 5 and 8 of the specification).
4. The present application provides the serine protease variants include variants in which the amino acids at positions corresponding to the 12th and 116th amino acids from the N-terminus of the SEQ ID NO: 31 are each substituted with a different amino acid in the amino acid sequence as set forth in SEQ ID NO: 31 or amino acid sequences having at least 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% homology or identity with the amino acid sequence of SEQ ID NO: 31 (see paragraph [0031]). The present specification further provides that specifically, among the above-described variants, the variants in which the amino acids at positions corresponding to the 12th and/or 116th amino acids of the amino acid sequence of SEQ ID NO: 31 are each substituted with a different amino acid may consist of any one amino acid sequence selected from the amino acid sequences of SEQ ID NOS: 32 to 39, without being limited thereto (see paragraph [0032]).
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Point 1, the amendment to the claims is insufficient to overcome the rejection as the required correlation between structure and function is still lacking.
With regard to Points 2 and 3, the Examples are limited to single or double amino acid mutants whereas the instant claims encompass mutations of up to 20% of the proteins sequence. Given that the protein of SEQ ID NO:31 is 187 amino acids in length, the instant claims encompass 2.06 x 1047 substitution mutants. Given the claims also encompass deletion and insertional mutant, the claimed genus of variant proteins is much larger. The limited disclosure of variants with the claimed biological characteristics is not deemed to be representative of the claimed genus. Hence, proper written description is lacking.
With regard to Point 4, the cited portions of the specification merely refers to variants with up to 20% sequence variation to SEQ ID NO:31 in a generalized and prophetic manner. The specification is silent with regard to what portions of the protein of SEQ ID NO:31 need to be present in order for said protein to have the claimed biological characteristics.
As outlined previously, the instant claims are drawn to variant serine proteases that have at least 80% sequence identity to SEQ ID NO:31 wherein said variant has a modification at position 12 and/or position 116. The specification discloses a variant Thermobifida fusca serine protease with substitutions at residues 12 and/or 116. Said variant meets the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph. However, the instant claims encompass 2.06 x 1047 substitution variants. Given that the rejected claims encompass not only substitution mutants but insertional and deletion mutants as well, the claimed genus of variant serine proteases based on SEQ ID NO:31 is much larger. None of these variant serine proteases meet the written description requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
To fulfill the written description requirement, Applicant must describe what residues must be present in order for a given variant to function as a serine protease. With the exception of the aforementioned variants, the specification is silent with regard to which combination of mutations would result in a functional serine protease.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
MPEP 2163.02 further states, “[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention” See, e.g., Pfaff v. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304, 312, 48 USPQ2d 1641, 1647 (1998); Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997); Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) (one must define a compound by "whatever characteristics sufficiently distinguish it"). Moreover, because the claims encompass a genus of variant species, 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 Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Additionally, MPEP 2163 states:
"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)”
And:
For inventions 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. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
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, 257:1306-1310) 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 (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. of Cell Bio. 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 Lazar et al. (Molecular and Cellular Biology, 1988, 8:1247-1252) 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. Bork (Genome Research, 2000, 10:398-400) disclose that 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). Clearly, given not only the teachings of Bowie et al., Lazar 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 functional variants of the polypeptide of SEQ ID NO:31 cannot be predicted. Clearly, it could not be predicted that a polypeptide that is a “variant” of a given SEQ ID NO: will function in a given manner. Reasonable correlation must exist between structure and function. In the instant case there is no correlation between the structure (i.e. sequence) of a given modified mycoplasma protein M and its recited function (inducing increased or unaltered thermostability). The specification, however, fails to disclose which amino acid residues of a given modified mycoplasma protein M are essential for the reciting biological functions or which amino acids might be added, replaced or deleted so that the resultant polypeptide retains the immunological characteristics of its parent, or by which other amino acids the essential amino acids might be replaced with so that the resultant peptide retains the Applicant must describe the sequence of the unmutated mycoplasma protein M but also describe which mutations which would result in the claimed biological activity. With the exception of the variant consisting of SEQ ID NO:31 with mutations at position 12 and 116, the specification is silent with regard to which combination of mutations would result in a functional serine protease. Consequently, the specification, does not disclose distinguishing and identifying features of a representative number of members of the genus of variant serine proteases which the claims are drawn, such as a correlation between the structure of the modified serine protease variant and its recited function, so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of antibodies. As evidenced by the teachings of Skolnick et al., the art is unpredictable. Skolnick et al. (Trends in Biotechnology 18: 34-39, 2000) discloses the skilled artisan is well aware that assigning functional activities for any particular protein or protein family based upon sequence homology is inaccurate, in part because of the multifunctional nature of proteins (see, e.g., the abstract; and page 34, Sequence-based approaches to function prediction). Even in situations where there is some confidence of a similar overall structure between two proteins, only experimental research can confirm the artisan's best guess as to the function of the structurally related protein (see, in particular, the abstract and Box 2). Thus, one skilled in the art would not accept the assertion, which is based only upon an observed similarity in amino acid sequence, that a variant of a given polypeptide would necessarily possess a given biological characteristic.
Given the skilled artisan would not be able to predict whether a given variant serine protease would have the claimed characteristics, there is no correlation between structure and function as required by the written description requirements. Consequently, proper written description is lacking.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 April 24, 2026
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