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 7-7-2026 is acknowledged. Claims 1 and 8 have been amended. Claims 3-6 have been canceled. Claims 1-2 and 7-9 are pending. Claims 2, 7 and 9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1and 8 are currently under examination.
Claim Objections Withdrawn
The objection of claim 6 for utilizing the abbreviation for the genus/species name “Escherichia coli” without defining it upon its first recitation is withdrawn in light of the amendment thereto.
Claim Rejections Withdrawn
The rejection of claims 1 and 3-6 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112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement is withdrawn in light of the amendment to claim 1 and the cancellation of claims 3-6.
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 claim 8 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 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. As amended, claim 1, as amended, recites "[a] transformed Escherichia coli (E. coli) strain" rather than the previously recited generic "microbial strain." Claim 1 further specifies disruption of the "endogenous ggt gene" encoding y-glutamyltransferase and the "endogenous gpmA gene" encoding phosphoglycerate mutase, together with enhanced expression of a gshA gene encoding
glutamate-cysteine ligase and/or a gshB gene encoding glutathione synthetase, or a gshF gene encoding bifunctional glutathione synthetase.
2. Claim 8, as amended, recites "[a] transformed Escherichia coli (E. coli) strain" and specifies disruption of the "endogenous ggt gene" and the "endogenous gpmA gene," while increasing the sequence identity threshold from 80% to 90% for each of the recited polypeptides. These amendments directly address the Examiner's concern that the original claims "encompass all types of microbes including all bacterial, fungal and yeast species/strains and a myriad of genes with differing sequences from a myriad of differing sources."
3. The specification identifies E. coli as "particularly preferable" as the host strain. As-Filed Specification, paragraph [0014]. The specification further states that "E. coli strains used as hosts are not particularly limited, and the E. coli K12 strains or E. coli strains derived from the K12 strains are preferable," and lists multiple strains including "DH10B, BW25113, DH5a, MG1655, JM109, and W3110 strains.".
4. Claim 8 does not merely recite polypeptides with 90% or higher sequence identity to the specified SEQ ID NOs. Rather, claim 8 requires that each polypeptide actually has the specified enzymatic activity, including y- glutamyltransferase activity, phosphoglycerate mutase activity, glutamate-cysteine ligase activity, glutathione synthetase activity, or bifunctional glutathione synthetase activity. Non- functional variants are excluded from the scope of claim 8. Unlike the scenario described by Skolnick et al. and Bowie et al. cited in the Office Action, where function is predicted from sequence alone, claim 8 requires that each polypeptide demonstrably possesses the recited enzymatic activity, thereby distinguishing claim 8 from the scenarios those references describe. The specification at paragraph [0019] expressly supports 90% sequence identity for y- glutamyltransferase, describing "a polypeptide consisting of an amino acid sequence having 80% or higher, preferably 85% or higher, and more preferably 90% or higher... sequence identity to the amino acid sequence as shown in SEQ ID NO: 22 and having y-glutamyltransferase activity."
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Point 1, claim 1 is not part of the rejection and hence Applicant’s arguments are not germane.
With regard to Point 2, the amendment to claim 8 is insufficient to overcome the rejection as there is still no correlation between structure (i.e. the sequences encoded by the recited genes) and function (i.e. recited activity of the encoded polypeptides).
With regard to Point 3, the basis of the rejection is not the choice of E. coli as the transformant but the lack of correlation between structure (i.e. the sequences encoded by the recited genes) and function (i.e. recited activity of the encoded polypeptides).
With regard to Point 4, while one would be able to envision polypeptides that fall within the claimed genus, they cannot predict which of those would have the claimed biological activity. The cited references demonstrate the unpredictability in determining variants of a given sequence that possesses a given biological characteristic. Given, that the instant claims encompass 1 x 6565 substitution variants of SEQ ID NO74; the claims also encompass insertion and deletion variants; the claims encompass additional variant genes (i.e. SEQ ID NO:72, 76, 22, and 20); the limited disclosure of the BW25113AggtApepTAgorAyliABCDAtnaAAspeC PompF-cysE/pQEK1-PT5-ABTd*-term strain and the BW25113AggtApepTAgorAyliABCDAtnaAAspeC PompF-cysE AgpmA/pQEK1-PT5-ABTd*-term strains is not deemed to be representative of the claimed genus of recombinant E. coli strains.
The rejected claims are drawn to transformed E. coli strain having a disruption of ggt and gpmA genes and the enhanced expression of gshA, gshB and cysE genes wherein the ggt gene produces a protein with at least 90% sequence identity to SEQ ID NO:22 and having γ-glutamyltransferase activity, the gpmA gene produces a protein with at least 90% sequence identity to SEQ ID NO:20 and having phosphoglycerate mutase activity, the gshA gene produces a protein with at least 90% sequence identity to SEQ ID NO:74 and having glutamate-cysteine ligase activity, the gshB gene produces a protein with at least 90% sequence identity to SEQ ID NO:76 and having glutathione synthetase activity and the gshF gene that produces a protein with at least 90% sequence identity to SEQ ID NO:72 and having bifunctional glutathione activity.
Consequently, the rejected claims encompass all types of microbes including all bacterial, fungal and yeast species/strains and a myriad of genes with differing sequences from a myriad of differing sources.
To adequately describe the genus of recombinant microbial strains with the claimed genotypic and phenotypic characteristics, Applicant describe the variants of the recited polypeptides have the recited biological activities. However, the specification does not disclose distinguishing and identifying features of a representative number of members of the genus of recombinant microbial strains to which the claims are drawn, such as a correlation between the structure of the microbial species (i.e. genome and phenotype) and its recited function (i.e. the recited enzyme functions) so that the skilled artisan could immediately envision, or recognize at least a substantial number of members of the claimed genus of recombinant microbial species. Moreover, the specification is silent with regard to what species a given gene encoding a given enzyme is derived from. The specification is limited to the stepwise production of two recombinant strains based on the E. coli BW25113 (i.e. the BW25113AggtApepTAgorAyliABCDAtnaAAspeC PompF-cysE/pQEK1-PT5-ABTd*-term strain and the BW25113AggtApepTAgorAyliABCDAtnaAAspeC PompF-cysE AgpmA/pQEK1-PT5-ABTd*-term strain). Said disclosure cannot be extrapolated to the full scope of the recombinant microbial species encompassed by the rejected claims. The specification is completely silent with regard to any microbial strain with the elected gene modifications. Therefore, since the specification fails to adequately describe at least a substantial number of members of the genus of recombinant microbial strains to which the claims refer and hence fails to meet the written description requirements as set forth int 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
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.).
Moreover, the describing of a biological entity by their functions was addressed in the Centocor decision (CENTOCOR ORTHO BIOTECH, INC. v ABBOTT LABORATORIES (Fed Cir, 2010-1144, 2/23/2011)). In said case the court stated”
To satisfy the written description requirement, "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,' and demonstrate that by disclosure in the specification of the patent." Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008) (quoting Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir. 1991)). Assessing such "possession as shown in the disclosure" requires "an objective inquiry into the four corners of the specification." Ariad, 598 F.3d at 1351. Ultimately, "the specification must describe an invention understandable to [a person of ordinary skill in the art] and show that the inventor actually invented the invention claimed." Id. A "mere wish or plan" for obtaining the claimed invention is not adequate written description. Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1566 (Fed. Cir. 1997).
The court further opined that Centocor's suggestion
that our decision in Noelle and the PTO written description guidelines support the view that fully disclosing the human TNF-α protein provides adequate written description for any antibody that binds to human TNF-α. That suggestion is based on an unduly broad characterization of the guidelines and our precedent.
The court concluded that
While our precedent suggests that written description for certain antibody claims can be satisfied by disclosing a well-characterized antigen, that reasoning applies to disclosure of newly characterized antigens where creation of the claimed antibodies is routine. Claiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described.
It is well established (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 have a given biological activity. Moreover, 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 (see 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. Clearly, variant proteins based on any of the sequence recited in claim 8 that maintained the recited biological characteristics of the parent could not be predicted. 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). 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 polypeptides of SEQ ID NO:20, 22, 72, 74 and 78 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.
New Grounds of Rejection
Claim1 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rendered vague and indefinite by the use of the phrase “…and enhanced expression of the gene [3] and [4]…”. It is unclear what constitutes “the gene” when [3] encompasses the plurality of genes (i.e. a gshA gene encoding glutamate-cysteine ligase and agshB gene encoding glutathione synthetase). As written it is impossible to determine the metes and bounds of the claimed invention.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 September 12, 2026
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