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 .
Detailed Action
Claims 1-20 are pending and now under consideration.
Priority
Applicants’ claim for the benefit of priority under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged. This application is a 371 of PCT/US2022/034720 filed on 06/23/2022, which claims benefit of Provisional application 63/214,304 filed on 06/24/2021.
Information disclosure statement
The information disclosure statement (IDS) submitted on 03/19/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS statement is considered and initialed by the examiner.
Objections-Abstract/Specification
I. The Abstract of the disclosure is objected to because, Abstract should be on a separate sheet of paper. The abstract of the disclosure is objected to because the abstract is presented as part of the first page of a WO publication. The abstract should be presented as a single sheet apart from all other bibliographic material including the information included on the first page of a WO publication. If EFS is used to submit a replacement abstract, the appropriate abstract (ABST) document code should be used for the one-page document. Correction is required. See MPEP § 608.01 (b).
II. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
I. Claim 1 and claim 2-20 depending therefrom recites subject-matter in parentheses i.e., “(modified cell)” in claim 1; it is not clear whether the subject-matter recited in parentheses is a limitation of claim 1 or merely exemplary; examiner urges the applicants’ to make a direct reference and not recite the limitation in parentheses. Furthermore, the preamble of the claim already recites “genetically modified yeast cell” and thus the subject-matter in parentheses is confusing and redundant.
II. Claims 4 and 14 is objected to, due to the following informality: Claim 4 recites the phrase “a sequence set forth in SEQ ID NO: 1” and claim 14 recites the phrase “a sequence set forth in SEQ ID NO: 2”; as such, given that the claim language recites “a sequence”, as the use of the indefinite article and “a” implies that there is more than one sequences of SEQ ID NO: 1 and SEQ ID NO: 2 and thus makes it unclear; claims 4 and 14 is deemed to encompass and reads on any subsequence within SEQ ID NO: 1 and SEQ ID NO: 2, as well as the full length sequence. It is suggested that “a” be replaced with “the”. The scope of the claims are unclear, as such it is unclear how homologous/identical to the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, a sequence of interest must be to be included within the scope of the claims and furthermore, it is not clear whether a full-length or a partial fragment of SEQ ID NO: 1 and SEQ ID NO: 2 is encompassed within the scope of the claims. Clarification and correction is required. For examination purposes, claims 4 and 14 is interpreted to encompass amino acid sequences having any percentage homology/similarity to said sequences and having methylglyoxal reductase (GRE2) and D-lactate dehydrogenase (D-LDH) activities. Examiner suggests amending the claim to recite “…comprising the amino acid sequence of SEQ ID NO: 1”; and recite “…comprising the amino acid sequence of SEQ ID NO: 2”. For examination purposes claims 4 and 14 is interpreted to encompass variants and mutants of the recited sequence(s) having undefined structural similarity/homology and the scope and breadth of the claimed sequences is not clear.
III. Recitation of “and/or” in claim 5 and claims 6-14 depending therefrom makes the claim indefinite, as it is not clear what limitations must be present. Correction and clarification is required. Examiner suggests amending the claim to recite “…or …”.
Claim Rejections: 35 USC § 112(b)
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
I. Claims 2 (claims 3-4 depending therefrom); and claims 13 (claim 14 depending therefrom) 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 pre-AIA the applicant regards as the invention.
Claims 2 and 13 are indefinite in the recitation of “derived”. The metes and bounds of the term “derived” is not clear in the context of the claim. It is not clear to the examiner what are the structures encompassed in “derived”? or is a representative member of a genus/merely exemplary. Furthermore, in claims 2 and 13 are indefinite in the recitation of “derived”; as written, one cannot determine if the term refers to ‘functions of several real variables” or ‘structural variables’ of claimed “derived” genes (unlimited structures or structurally undefined molecules or functionally variable molecules and the extent of variability is unclear). The metes and bounds of the claims are unclear. For examination purposes, no patentable weight will be given to the terms. It is not clear to the examiner as to what the phrase “derived” means in the context of the above claims, is this synonymous with “obtained from specific source or having specific structures? or does it include natural and man-made variants of unlimited/undefined structures thereof from any source? Examiner suggests amending the claims to recite ”obtained from…”. Clarification and correction required.
II. Claims 4 and 14 are 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 pre-AIA the applicant regards as the invention.
Claim 4 is indefinite in the recitation of phrase “a sequence set forth in SEQ ID NO: 1” and claim 14 is indefinite in the recitation of phrase ”a sequence as set forth in SEQ ID NO: 2”; as such, given that the claim language recites “a sequence”, as the use of the indefinite article and “a” implies that there is more than one amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2 and thus makes it unclear; claims 4 and 14 is deemed to encompass and reads on any subsequence within SEQ ID NO: 1 and SEQ ID NO: 2, as well as the full length sequences. It is suggested that “a” be replaced with “the”. The scope of the claims are unclear, as such it is unclear how homologous/identical to the amino acid sequences of SEQ ID NO: 1 and SEQ ID NO: 2, a sequence of interest must be to be included within the scope of the claims and furthermore, it is not clear whether a full-length or a partial fragment of SEQ ID NO: 1 and SEQ ID NO: 2 is encompassed within the scope of the claims. For examination purposes, claims 4 and 14 is interpreted to encompass amino acid sequences having any percentage homology/similarity to said sequences and having methylglyoxal reductase (GRE2) and D-lactate dehydrogenase (D-LDH) activities. Examiner suggests amending the claim to recite “…comprising the amino acid sequence of SEQ ID NO: 1; and comprising the amino acid sequence of SEQ ID NO: 2”. Appropriate correction is required.
III. Claim 5 and claims 6-14 depending therefrom 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 pre-AIA the applicant regards as the invention; recitation of “and/or” in claim 5 makes the claims indefinite, as it is not clear what limitations must be present. The metes and bounds of claim 5 and claims 6-14 depending therefrom are not clear and thus, it would not be possible to one of ordinary skill in the art to define the metes and bounds of the desired patent protection. The rejection may be overcome by amending the claims to recite “… or …”. Correction and clarification is required. Examiner suggests amending the claim to recite “…or …”.
IV. Claim 10 (claims 11-14 depending therefrom); and claims 17-19 and (claim 20 depending therefrom) are 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 pre-AIA the applicant regards as the invention.
Regarding claims 10, 14 and 17-19, the phrase "optionally" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949).
In the present instance, claim 10 recites the broad recitation “Saccharomyces” and the claim also recites “…optionally wherein the yeast cell is of the species Saccharomyces cerevisiae” which is the narrower statement of the range/limitation (range within range); claim 14 recites the broad recitation “comprises a sequence having at least 90% identity to the amino acid sequence set forth in SEQ ID NO: 2” and the claim also recites “optionally wherein the enzyme having D-LDH activity comprises a sequence as set forth in SEQ ID NO: 2” which is the narrower statement of the range/limitation (range within range); claim 17 recites the broad recitation “wherein the potassium salt is selected from potassium phosphate monobasic (KH2PO4), potassium bicarbonate (KHCO3), potassium phosphate dibasic (K2HPO4), potassium chloride (KCl), potassium hydroxide (KOH), and potassium sulfate (K2SO4)” and the claim also recites “optionally wherein the potassium salt is K2HPO4” which is the narrower statement of the range/limitation (range within range); claim 18 recites the broad recitation “concentration of potassium salt in the medium is between about 15 mM to about 200 mM” and the claim also recites “optionally wherein the concentration of potassium salt in the medium is about 50 mM” which is the narrower statement of the range/limitation (range within range); and claim 19 recites” pH modulator is selected from potassium hydroxide (KOH), potassium phosphate dibasic (K2HPO4), and calcium carbonate (CaCO3)” and the claim also recites “optionally wherein the pH modulator is CaCO3” which is the narrower statement of the range/limitation (range within range). It is not clear what the applicants’ intend to encompass in the rejected claims and the metes and bounds of the claims are unclear and as being indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired; as being indefinite because it is not clear whether the recitation following “optionally” is limiting. See MPEP 2173.05(h), which makes clear that “optionally” is another alternative format which requires some analysis before concluding whether or not the language is indefinite. In this regard, the term “optionally” in the context of the claim is analogous to the term “preferably.” When interpreted in this manner, it is unclear whether this narrower limitation following the recitation “optionally” is limiting. See MPEP 2173.05(d). Examiner suggests applicants’ consider writing additional new claims as dependent claims.
Claim Rejections: 35 USC § 112(a)
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
I. Claims 1-2 and 4-13 and 15-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, as containing 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(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-2 and 4-13 and 15-20 as interpreted is directed to encompass: any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20).
In University of California v. Eli Lilly & Co., 43 USPQ2d 1938, the Court of Appeals for the Federal Circuit has held that “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials”. As indicated in MPEP § 2163, 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, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 that Applicant was in possession of the claimed genus. In addition, MPEP § 2163 states that a representative number of species means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In the instant case the scope of the instant claims encompass a genus of structures (no structural limitation) for polypeptides and the encoding polynucleotides of interest with associated function, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20).
No information, beyond the characterization of an isolated methylglyoxal reductase (GRE2) having the amino acid sequence of SEQ ID NO: 1 and specific variants of SEQ ID NO: 1; and an isolated D-lactate dehydrogenase (D-LDH) having the amino acid sequence of SEQ ID NO: 2 and method of use in specific cellular context Saccharomyces cerevisiae for the utilization of xylose in feedstocks comprising furfurals and hydroxymethyl-furfurals (HMF; see Examples 1-2, pages 15-41 of specification), has been provided by the applicants’, which would indicate that they had possession of the claimed genus of structures (no structural limitation) for polypeptides of interest with associated function and their encoding polynucleotides, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20).
The art also teaches, even highly structurally homologous polypeptides do not necessarily share the same function and conversely functionally similar molecules do not necessarily have similar structures. For example proteins having similar structure have different activities; Witkowski et al., (Biochemistry 38:11643-11650, 1999; reference provided in parent application 11/206,810) teaches that one conservative amino acid substitution transforms a b-ketoacyl synthase into a malonyl decarboxylase and completely eliminates b-ketoacyl synthase activity. Similarly, Wishart et al., (J. Biol. Chem., 1995, Vol. 270(10): 26782-26785) teach that a single mutation converts a novel phosphotyrosine binding domain into a dual-specificity phosphatase. The art also teaches that functionally similar molecules have different structures; Kisselev L., (Structure, 2002, Vol. 10: 8-9) teach that polypeptide release factors in prokaryotes and eukaryotes have same function but different structures.
Hence, the recited genera of polypeptides and the encoding polynucleotides are interpreted to have widely variable structures, since minor changes may result in changes affecting function and no additional information correlating structure with function has been provided.
Therefore, given the lack of description of representative species encompassed by the genus of polypeptides, encoding polynucleotides and modifications, the specification fails to sufficiently describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize that applicants’ were in possession of the claimed invention. Applicants’ are referred to the revised guidelines concerning compliance with the written description requirement of 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Enablement
II. Claims 1-2 and 4-13 and 15-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for characterization of an isolated methylglyoxal reductase (GRE2) having the amino acid sequence of SEQ ID NO: 1 and specific variants of SEQ ID NO: 1; and an isolated D-lactate dehydrogenase (D-LDH) having the amino acid sequence of SEQ ID NO: 2 and method of use in specific cellular context Saccharomyces cerevisiae for the utilization of xylose in feedstocks comprising furfurals and hydroxymethyl-furfurals (HMF; see Examples 1-2, pages 15-41 of specification), does not reasonably provide enablement for a genus of structures (no structural limitation) for polypeptides and the encoding polynucleotides of interest with associated function, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20). 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 or use the invention commensurate in scope with the claim.
Factors to be considered in determining whether undue experimentation is required are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claims 1-2 and 4-13 and 15-20 are so broad as to encompass: a genus of structures (no structural limitation) for polypeptides and the encoding polynucleotides of interest with associated function, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20). The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number polypeptides and encoding polynucleotides broadly encompassed by the claims. Since the amino acid sequence of a protein encoded by a polynucleotide determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires knowledge and guidance with regard to which amino acids in the protein's sequence and the respective codons in its polynucleotide, if any, are tolerant of modification and which are conserved (i.e., expectedly intolerant to modification), and detailed knowledge of the ways in which the encoded proteins' structure relates to its function. In view of the broad breadth of the claims, the amount of experimentation required to determine the structure of all the polypeptides or the encoding polynucleotides from any plant source including variants, mutants and recombinants, the lack of guidance, working examples, and unpredictability of the art in predicting function from a polypeptide primary structure (e.g., see Whisstock et al., Q Rev Biophys. 2003 Aug; 36(3): 307-340; reference provided in parent application 11/206,810), practicing the claimed invention would require undue experimentation. As such, the specification fails to enable the entire scope of the claimed invention.
However, in this case the disclosure is limited to characterization of an isolated methylglyoxal reductase (GRE2) having the amino acid sequence of SEQ ID NO: 1 and specific variants of SEQ ID NO: 1; and an isolated D-lactate dehydrogenase (D-LDH) having the amino acid sequence of SEQ ID NO: 2 and method of use in specific cellular context Saccharomyces cerevisiae for the utilization of xylose in feedstocks comprising furfurals and hydroxymethyl-furfurals (HMF; see Examples 1-2, pages 15-41 of specification), but provides no guidance with regard to the making and using of a genus of structures (no structural limitation) for polypeptides and the encoding polynucleotides of interest with associated function, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20) or with regard to other uses. In view of the great breadth of the claims, amount of experimentation required to make the claimed polypeptides and encoding polynucleotides, the lack of guidance, working examples, and unpredictability of the art in predicting function from a polypeptide primary structure (e.g., see Whisstock et al., Q Rev Biophys. 2003 Aug; 36(3): 307-340), the claimed invention would require undue experimentation. As such, the specification fails to teach one of ordinary skill how to make and use the full scope of polypeptides and encoding polynucleotides encompassed by the claims.
While enzyme isolation techniques, recombinant and mutagenesis techniques are known, and it is not routine in the art to screen for multiple substitutions or multiple modifications as encompassed by the instant claim, the specific amino acid positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions or deletions.
The specification does not support the broad scope of the claims which encompass: a genus of structures (no structural limitation) for polypeptides and the encoding polynucleotides of interest with associated function, i.e., any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20), because the specification does not establish: (A) regions of the protein/polynucleotide structure which may be modified without affecting the activity of the encoded methylglyoxal reductase (GRE2) and D-lactate dehydrogenase (D-LDH); (B) the general tolerance of the polypeptide and the polynucleotide encoding methylglyoxal reductase (GRE2) and D-lactate dehydrogenase (D-LDH) to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue or the respective codon in the polynucleotide with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful.
Thus, applicants’ have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claim broadly including polypeptides and encoding polynucleotides with an enormous number of modifications including variants, mutants and recombinants of undefined structure with the associated function. The scope of the claim must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of polypeptides having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
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 to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The breadth of claims includes overly broad genus, applicants’ disclose no direction or guidance on how to design and make any polypeptide and the encoding polynucleotide of undefined structure having desired activity as noted in the breadth above. Thus, instant specification and prior art failed to describe how to make and use the claimed genus of polypeptides and encoding polynucleotides sufficiently. Although, it is possible to display and create any protein structure in computer (in silico) and manipulate in any possible way, such as inserting any amino acid(s) into preexisting three-dimensional scaffold; the creation of desired catalytic/biologic activity in a solution is highly unpredictable.
According to MPEP § 2164.02: “All questions of enablement are evaluated against the claimed subject matter. The focus of the examination inquiry is whether everything within the scope of the claim is enabled.”; “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). Nevertheless, not everything necessary to practice the invention need be disclosed. In fact, what is well-known is best omitted. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991). All that is necessary is that one skilled in the art be able to practice the claimed invention, given the level of knowledge and skill in the art. Further the scope of enablement must only bear a “reasonable correlation” to the scope of the claims. See, e.g., In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).”; and “As concerns the breadth of a claim relevant to enablement, the only relevant concern should be whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate with the scope of protection sought by the claims. > AK Steel Corp. v. Sollac, 344 F.3d 1234, 1244, 68 USPQ2d 1280, 1287 (Fed. Cir. 2003); < In re Moore, 439 F.2d 1232, 1236, 169 USPQ 236, 239 (CCPA 1971). See also Plant Genetic Sys., N.V. v. DeKalb Genetics Corp., 315 F.3d 1335, 1339, 65 USPQ2d 1452, 1455 (Fed. Cir. 2003) (alleged “pioneer status” of invention irrelevant to enablement determination).”
Instant claims are so broad such that, instant disclosure of instant specification and a general knowledge in the art are not commensurate with the scope of instant claims for one skilled in the art to make and use claimed invention without undue experimentation. As noted above, the breadth of instant claims encompass an overly broad genus of undefined structure including variants, mutants and homologs.
Therefore, taking into consideration the extremely broad scope of the claims, the lack of guidance, the amount of information provided, the lack of knowledge about a correlation between structure and the desired function, and the high degree of unpredictability of the prior art in regard to structural variability and its effect on function, one of ordinary skill in the art would have to go through the burden of undue experimentation in order to practice the claimed invention. Thus, applicants’ have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims. The scope of the claim must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of any gene encodes an enzyme having methylglyoxal reductase (GRE2) activity including variants, mutants and recombinants (no structure is provided, as in claims 1-2); “a sequence set forth in SEQ ID NO: 1” (claims 4); any gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity including variants, mutants and recombinants (no structure is provided, as in claims 12-13); “a sequence as set forth in SEQ ID NO: 2” (claim 14); as such, the term “a nucleotide sequence” in broadest reasonable interpretation encompasses not only SEQ ID NO: 1 and SEQ ID NO: 2 but any fragment/subsequences within SEQ ID NO: 1 and SEQ ID NO: 2 (also see claims objections and 35 U.S.C. 112(b) rejection above for claims interpretation); and a method of producing biofuel (as in claims 15-20), is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Claim Rejections: 35 USC § 102 (AIA )
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.
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 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.
Claims 1-4 and 10-11 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133) and disclose an engineered xylose-fermenting S. cerevisiae in xylose and/or glucose media; and elucidated that glycolaldehyde and methylglyoxal are the key inhibitory short-aliphatic aldehydes on engineered xylose-fermenting S. cerevisiae in xylose containing medium and the degree of toxicity of these tested fermentation inhibitors varies with the sole carbon source of the medium. Said reference demonstrates that genetically modified S. cerevisiae via genome integration of an extra copy of autologous GRE2 with its native promotor (as evidenced by UniProtKB/Swiss-Prot database Accession#Q12068, discloses autologous GRE2 is methylglyoxal reductase enzyme and comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 1 of the instant invention; see provided sequence alignment) substantially improved the toxic tolerance of engineered xylose-fermenting S. cerevisiae to major inhibitory compounds including glycolaldehyde in the xylose-containing medium, and xylose-rich, lignocellulosic hydrolysate and concurrently improved the ethanol/biofuel fermentation profile (see Abstract; and entire document); said reference genetically modified S. cerevisiae is able to ferment xylose to ethanol in the absence of glucose; applicants’ are also directed to the following sections in by Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133): Results, pages 8124-8128; Tables 1-5; Fig. 1-4; and Discussion/Summary, col. 2, last paragraph, page 8131.
Therefore, the reference of Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133) is deemed to anticipate claims 1-4 and 10-11 as written and when given the broadest reasonable interpretation.
Claim Rejections: 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4 and 9-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133) as applied to claims 1-4 and 10-11 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) above) and further in view of Moon et al., (Enzyme Microb. Technol., 2012, Vol. 50: 115-120), Lam et al., (Science, 2014, Vol. 346(6205): 71-75) and Mitsui et al., (Appl. Microbiol. Biotechnol., 2020, Vol. 104: 9147-9158).
The disclosure of Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133) as applied to claims 1-4 and 10-11 is described in the rejection 35 USC § 102/§ 103 above. However, Jayakody et al., is silent regarding wherein the promoter is selected from the group consisting of pTDH3, pTEF3, and pPDC1 (as in claim 9); further comprising a second exogenous gene, wherein the second exogenous gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity (as in claims 12-14); and a medium comprising a potassium salt and a pH modulator… wherein the pH modulator is selected from potassium hydroxide (KOH), potassium phosphate dibasic (K2HPO4), and calcium carbonate (CaCO3), optionally wherein the pH modulator is CaCO3 (as in claims 15-20).
Regarding claims 1-4 and 10-11, Moon et al., (Enzyme Microb. Technol ., 2012, Vol. 50: 115-120) also disclose a genetically engineered yeast/S. cerevisiae comprising and over-expressing wild-type and variants of GRE2 gene obtained from S. cerevisiae, and said genetically engineered yeast/S. cerevisiae is tolerant to inhibitory compounds like furfural and HMF and able to grow in synthetic medium comprising said inhibitory compounds like furfural and HMF (see Abstract; Tale 2, Fig. 1, page 117; Fig. 3-4 and Table 3, page 118; and entire document).
Regarding claims 9 and 15-20, wherein the promoter is selected from the group consisting of pTDH3, pTEF3, and pPDC1 and a medium comprising a potassium salt and a pH modulator… wherein the pH modulator is selected from potassium hydroxide (KOH), potassium phosphate dibasic (K2HPO4); Lam et al., (Science, 2014, Vol. 346(6205): 71-75) provide teaching, suggestion and motivation to a skilled artisan for generating genetically engineered yeast/S. cerevisiae comprising/over-expressing potassium and proton pumps (Abstract; and entire document), wherein in said genetically engineered yeast/S. cerevisiae the genes of interest for expression is under the control of promoter pTEF3 (see Supplementary Materials Database S1, Plasmid Construction, pages 2-3); said genetically engineered yeast/S. cerevisiae able to utilize xylose as a substrate in the absence of glucose (Supplementary Materials Database S1, Media and Fermentation conditions Supplementary Materials Database S1, pages 3-4); said genetically engineered yeast/S. cerevisiae viability and alcohol tolerance increased in the presence of KCL/KOH and viability at a pH range of 3.6-5.8 (see Fig.1, page 72) and at a pH range 3.7-6.0 and conclude elevated potassium and pH are sufficient to enhance tolerance to sugar species and alcohol species (Fig. 2, page 73; Fig. 3-4, page 74; and entire document).
Regarding claims 12-14 and 20, further comprising a second exogenous gene, wherein the second exogenous gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity; Mitsui et al., (Appl. Microbiol. Biotechnol., 2020, Vol. 104: 9147-9158) and (as evidenced by UniProtKB/Swiss-Prot database Accession#Q2ABS1, discloses D-lactate dehydrogenase (D-LDH) enzyme obtained from Leuconostoc mesenteroides and comprising an amino acid sequence having 100% sequence identity to SEQ ID NO: 2 of the instant invention; see provided sequence alignment); Mitsui et al., provide teaching, suggestion and motivation to a skilled artisan for generating genetically engineered yeast/S. cerevisiae comprising/over-expressing D-lactate dehydrogenase (D-LDH) enzyme obtained from Leuconostoc mesenteroides (see Abstract; and entire document), as the reference D-lactate dehydrogenase (D-LDH) confers acid-tolerance in said reference genetically engineered yeast/S. cerevisiae and is able to tolerate at pH 3.5-6.5 (Table 2, page 9150; Fig. 1, page 9152); said acid-tolerant genetically engineered yeast/S. cerevisiae is able to grow and cultivated in YPD100 medium comprising 20g/L CaCO3 medium (semi-neutralizing condition; see Fig. 6, page 9155).
As such, disclosure of strategy and methods for the use of “the promoter is selected from the group consisting of pTDH3, pTEF3, and pPDC1; further comprising a second exogenous gene, wherein the second exogenous gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity; and a medium comprising a potassium salt and a pH modulator… wherein the pH modulator is selected from potassium hydroxide (KOH), potassium phosphate dibasic (K2HPO4), and calcium carbonate (CaCO3), optionally wherein the pH modulator is CaCO3”; as in claims 9 and 12-20 for generating genetically engineered yeast/S. cerevisiae tolerant to toxic furfural, HMF, pH tolerance and production of ethanol of the instant invention, such as that of references of Moon et al., Lam et al., and Mitsui et al., teaching the advantages of said modifications, clearly suggests to a skilled artisan to modify the teachings Jayakody et al., and incorporate the structural and functional elements of Moon et al., Lam et al., and Mitsui et al., in the claimed genetically modified yeast cell and a method for increased production of biofuel/ethanol as claimed in the instant invention. One of ordinary skill in the art would have a reasonable expectation of success, since the generation and use of genetically modified yeast cell and a method for increased production of biofuel/ethanol are well known in the art.
Regarding specific choice of encoding genes, alcohol tolerance increased in the presence of KCL/KOH and pH, are also provided/suggested in the combination of references, and examiner also takes the position the following position; optimization of known variables, and the examiner finds support in: MPEP 2144.05 [R-5]: A. Optimization Within Prior Art Conditions or Through Routine Experimentation Generally, differences in encoding genes, alcohol tolerance increased in the presence of KCL/KOH and pH etc., will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation". As to optimization results, a patent will not be granted based upon the optimization of result effective variables when the optimization is obtained through routine experimentation unless there is a showing of unexpected results which properly rebuts the prima facie case of obviousness. See In re Boesch, 617 F.2d 272,276,205 USPQ 215,219 (CCPA 1980). See also In re Woodruff, 919 F.2d 1575, 1578, 16 USPQ2d 1934, 1936-37 (Fed. Cir. 1990), and In re Aller, 220 F2d 454,456,105 USPQ 233,235 (CCPA 1955). Furthermore, "it is prima facie obvious to combine two or more compositions and methods each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition or third method to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Therefore, claims 1-4 and 9-20 are rejected under 35 U.S.C. 103(a) as being unpatentable over Jayakody et al., (Appl. Microbiol. Biotechnol., 2018, Vol. 102: 8121-8133) as applied to claims 1-4 and 10-11 (see 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) above) and further in view of Moon et al., (Enzyme Microb. Technol., 2012, Vol. 50: 115-120), Lam et al., (Science, 2014, Vol. 346(6205): 71-75) and Mitsui et al., (Appl. Microbiol. Biotechnol., 2020, Vol. 104: 9147-9158).
Allowable Subject Matter/Conclusion
None of the claims are allowable.
Art of Interest
Based on the granted priority (06/24/2021) for the instant application, Lam et al., (Sci Adv., 2021, Vol. 7: eabf/7613, pages 1-13, in IDS; published 06/25/2021) disclose a genetically modified yeast cell/S. cerevisiae comprising: a first exogenous gene operably linked to a promoter, wherein the first exogenous gene encodes an enzyme having methylglyoxal reductase (GRE2) activity and further comprising a second exogenous gene, wherein the second exogenous gene encodes an enzyme having D-lactate dehydrogenase (D-LDH) activity method of producing biofuel from toxic biomass. However, the cited art is not used in any rejection, because said reference has a later publication date.
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/GANAPATHIRAMA RAGHU/ Primary Examiner, Art Unit 1652