DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 2/24/2026 to claims 1, 5, 6, 9, and 23-28 have been entered. Claims 2-4, 7, 10, 11, and 18-22 are canceled. Claims 1, 5, 6, 8, 9, 12-17, and 23-29 remain pending, of which claims 9, 12, 14-16, and 23-28 are being considered on their merits. Claims 1, 5, 6, 8, 13, and 17 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claim 9 have overcome the new matter rejections of record under 35 U.S.C. § 112(a), which are withdrawn.
Any other rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 9, 12, 14-16, and 23-29 are rejected under 35 U.S.C. 101 because the claimed invention is directed to natural product without significantly more.
Claim 9 and its dependent claims recite a natural product, S. thermophilus. The S. thermophilus of claim 9 is described as suitable for use in food, wherein the mutant is derived from mother strain STCH_09 (DSM19243), STCH_12 (DSM32826), STCH_13 (DSM32841), STCH_14 (DSM21408), STCH_15 (DSM32842), comprising introducing by means of genetic engineering a mutation in one or more of the proteins encoded by SEQ ID NO:2, and recites product-by-process limitations towards mutating S. thermophilus and wherein the mutant strains carries a mutation such that expression of a protein encoded by a sequence having at least 98% sequence identity to one or more of SEQ ID NO:2 such that the mutant strain shows increased robustness against phage attacks. Claim 9 recites product-by-process limitations to deselect the mutant strains comprising a generic mutation in one of more of the CRISPR-region and a R/M region, wherein the mutant strains carries a mutation such that expression of a protein encoded by a sequence having at least 98% sequence identity to one or more of SEQ ID NO:2 is impaired, and wherein said mutation results in a change in glycan biosynthesis. Claim 23 recites wherein the mutant strain comprises a mutation in a gene involved in glycan synthesis, wherein the gene comprises a nucleotide sequence with at least 98% sequence identity to SEQ ID NO: 2 and wherein the selected phage resistant mutant strain shows increased robustness against phage attacks compared to its mother strain, as assessed using a Heap Lawrence assay. Claims 9, 12, 14-26, and 23-29 are directed towards generic mutations in SEQ ID NO 2. Claims 12, 14-16, 23-29 depend from or incorporate the natural product of claim 9.
Kouwen (WO 2015/124718; provided in the IDS dated 9/27/2021) makes clear that populations of S. thermophilus possess natural mutations that make this bacterium bacteriophage resistant (see p3, lines 11-15 and 25-26). A review of the disclosure as a whole suggests that Applicant has not generated any new mutant of S. thermophilus such as but not limited to plasmid transformation to confer a new functional property or treating the bacterium with a mutagenic compound, but has only selected from naturally-occurring mutations within a population of S. thermophilus (e.g., p13-14 of the specification at Example 1).
Therefore, there no evidence as yet of record that the claimed product possesses any markedly different characteristic than the natural product at this time. See M.P.E.P. § 2106.04(c). The product-by-process limitations of claim 9 don’t set forth any specific structure to the claimed bacterium that clearly sets forth any particular markedly different characteristic, nor does the claim recite any particular combination of structure and function that might otherwise rise to the level of a markedly different characteristic. The mutant strains are derived from the claimed mother strains, and so the mutant strains are necessarily generic as no specific mutation(s) are specified in the claims.
This judicial exception is not integrated into a practical application because Claims 9, 12, 14-16, 23-29 are only directed towards the natural product itself in the absence of any showing to the contrary and so do not recite any other limitation that could amount to significantly more than the judicial exception.
Regarding claims 9, 15 and 16, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Regarding claim 9, Sing et al. (Applied and Environmental Microbiology (1993), 59(2), 365-372) teaches that the Heap-Lawrence starter culture activity test was routine and conventional in this art; see Sing at the Abstract and “SATs” on p366-367. Regarding claim 15, Kouwen (WO 2015/124718; provided in the IDS dated 9/27/2021) teaches that freeze drying S. thermophilus would be routine and conventional in this art (p14, lines 17-21). Regarding claim 16, O’Leary (Applied and Environmental Microbiology (1976), 32(1), 89-94) teaches adding glucose is routine and conventional in this art (see the Abstract). The evidentiary teachings of Hyatt (J Bacteriol (1962), 83, 1231-1237) makes clear that glucose is reasonably construed as a species of germination booster/enhancer (See the Abstract of Hyatt).
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 9, 12, 14-16, and 23-29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites product-by-process limitations and recites a phage resistant strain of S. thermophilus, suitable for use in a food and comprising mutations in a gene comprising a nucleotide sequence with at least 98% sequenced identity to SEQ ID NO: 2 and wherein and wherein said mutation results in an increased robustness against phage attacks as compared to the mother strain. Claim 9 recites product-by-process limitations to deselect the mutant strains comprising a generic mutation in one of more of the CRISPR-region and a R/M region, and wherein the mutant strains carries a mutation such that expression of a protein encoded by a sequence having at least 98% sequence identity to SEQ ID NO:2 and results in a change in glycan synthesis. The mutant strains are derived from the claimed mother strains, and so the mutant strains are necessarily generic as no specific mutation(s) are specified in the claims. Claims 23-29 are directed towards generic mutations in one or more of SEQ ID NO: 1-6. Claims 12, 14-16, and 23-29 depend from or incorporate the limitations of claim 9
.
M.P.E.P. §2163 recites, “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 the applicant was in possession of the claimed genus…when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. 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.”
Random mutagenesis is one known method of creating genetic mutations in microorganisms such as S. thermophilus as encompassed by the claimed invention. This subject was generally reviewed in the context of directed enzyme evolution shortly after the invention was filed by Labrou (Current Protein and Peptide Science (2010), v11(1), p91-100). Labrou teaches that random mutagenesis is a directed evolution strategy, which introduces random point mutations into whole genes. Random mutagenesis mechanisms includes modifications which can be divided into five categories: (i) transitions, which involve substitution of a purine nucleotide by another purine, or a pyrimidine by a second pyrimidine, (ii) transversions, which involve substitution of a purine nucleotide by a pyrimidine, or vice versa, (iii) deletions, in which one or more nucleotides are deleted from a gene, (iv) insertions, in which one or more extra nucleotides are incorporated into a gene, and (v) inversions, which involve the 180º rotation of a double-stranded DNA segment of two base pairs or longer (p91, left column, sentence starting "Random mutagenesis is a directed evolution strategy..." through sentence ending in "...or longer [25]"). Labrou summarizes the known techniques of randomly mutating DNA in vitro or in situ: chemical mutagenesis, passing cloned genes through mutator strains, highly error-prone PCR mutagenesis, rolling circle error prone PCR, and saturation mutagenesis (p91, right column, sentence starting “There are many methods…). Labrou teaches frequently used chemical mutagens and the types of mutations caused in Table 1, and chemical mutagenesis is generally understood as the most cost-effective and simple method but also lacks efficient control of the mutation and a limited range of possible mutations (interpreted that some mutations would be "silent," i.e. would not effect change at the amino acid level) (p93, left column, paragraph starting “The advantage of chemical mutagenesis…”). Labrou teaches that mutator strains are useful for mutating recombinantly-introduced DNA (and protein) of interest because the strains have been engineered to lack the primary DNA repair pathways and so have about a 5000 fold higher mutation rate (p93, subheading “2.3 Mutator Strains”, first paragraph). Labrou teaches error-prone PCR is a method of increasing the error rate of Taq polymerase, already lacking 3'-5' exonuclease activity and thus having an error rate of about 1 x 104 base substitutions/base pair of product, by changing the PCR reaction conditions such as increasing the concentration of Mn2+ (p94-95, subheading “2.4 “Error-Prone” PCR, first paragraph). Labrou teaches site-saturation mutagenesis is a method of screening all 20 naturally-occurring amino acids at a specific amino acid residue of interest within a polypeptide (p95, subheading “2.6 Site-Saturating Mutagenesis”, first paragraph).
While the types of mutations that may change the nucleotide structure of DNA are readily known and the associated methods of randomly mutagenizing DNA and making new bacterial strains are taught by Labrou, the exact site of any particular nucleotide mutation is inherently and necessarily random and thus entirely unpredictable. Underlying the teachings of Labrou is that while the average rate of random mutation may be known or may be calculated, the probability of any particular nucleotide being mutated is independent of time and of other nucleotides (i.e. a Poisson distribution).
Kouwen (WO 2015/124718; provided in the IDS dated 9/27/2021) teaches that populations of S. thermophilus possess natural mutations that make this bacterium bacteriophage resistant (see p3, lines 11-15 and 25-26), and also methods of making bacteriophage insensitive mutants (BIMs) of S. thermophilus (Example 1). Kouwen teaches generating the BIMs by adding phage lysate from specific phages to the parent S. thermophilus strain (p17-18,. Subheading 3.1). Kouwen does not particularly identify any specific mutations that correlate to the property of phage resistance as measured by an increased sedimentation rate, increased chain formation, and/or reduced phage adsorption but speculates the mutations are likely in the cell envelope and/or phage receptor binding site and are mechanistically related to the endogenous CRISPR-1, CRISPR-2, and CRISPR-3 (Example 1; see p2-3 for a brief review of endogenous CRISPR systems in S. thermophilus; p6, lines 9-23).
In methods of making mutants of S. thermophilus by randomly mutagenizing the parent S. thermophilus strain or contacting the parent S. thermophilus strain with phage lysate to yield phage resistant strains for claim 9, and derivation of generic strains from the Markush group of mother strains for claim 9, there is no reasonable expectation that the same mutations would be generated or selected for using the same method on two populations of the parent strain. Therefore, Labrou and Kouwen (continue to) set forth a prima facie case for unpredictability to correlate the structure of the claimed S. thermophilus strains carrying a mutation in a gene having at least 95% sequence identity to SEQ ID NO: 2 with the functional property of phage resistance and for any particular mutation that impairs any protein encoded by the nucleotide sequence with at least 98% sequence identity to SEQ ID NO: 2 and wherein said mutation results in any change in glycan synthesis.
In the instant case, the broadest reasonable interpretation of the claims is towards entirely generic towards any mutation in the nucleic acid sequences of claim 9 such as to directly or indirectly confer phage resistance in S. thermophilus, and a mutation that results in a change in glycan synthesis. However, the specification only describes the species of specific amino acid mutations set forth in Table 2 as being capable of conferring phage resistance in S. thermophilus. Table 2 does not set forth any changes to the expression of SEQ ID NO: 2 as set forth in claim 9, claim 9 is not limited to any particular mutation in any nucleotide or amino acid sequence combined with the claimed property of resistance towards any particular species of phage, no other species of mutations are disclosed, and Applicant's description of the mutations in Table 2 suggests that these specific amino acid mutations would have specific functional properties with respect to claimed property of changing glycan biosynthesis and the disclosed property of bacteriophage insensitivity in S thermophilus.
Therefore, the original disclosure at this time does not set forth a sufficient number of “representative species” and any particular structure-function correlation to support the expansive scope of the claims. Applicant has not described how the functional property of altering glycan biosynthesis in S. thermophilus correlates to other species comprising any possible genetic mutation in S. thermophilus to show possession of the entire genus.
Claims 12, 14-16, 23-29 depend from or incorporate the subject matter of claim 9 and does not further limit the genus of mutations of claim 9, and so must be rejected with claim 9 for lacking adequate written description.
Response to Arguments
Applicant's arguments on pages 6-8 of the reply have been fully considered, but not found persuasive of error for the reasons given below.
On pages 6-7 of the reply, Applicant alleges that the instant amendments to claim 6 have overcome the 35 U.S.C. § 101 rejections of record. This is not found persuasive because Kouwen makes clear that phage resistance occurs naturally, and so the burden remains with Applicant to 1) show a markedly different characteristic of the claimed phage-resistance mutant S. thermophilus strains as compared to the substantially identical and naturally-occurring strains of phage-resistance strains of S. thermophilus strains of Kouwen, or 2) amend the claims to clearly and specifically recite a markedly different characteristic, such as but not limited to specific genetic mutations that could not be found in Kouwen. For example, the specific mutations of table 2 of the disclosure are not presently claimed such that they could be considered as a markedly different characteristic at this time. A review of the disclosure as a whole suggests that Applicant has not generated any new mutant of S. thermophilus such as but not limited to plasmid transformation to confer a new functional property or treating the bacterium with a mutagenic compound, but has only selected from naturally-occurring mutations within a population of S. thermophilus (e.g., p13-14 of the specification at Example 1). As such, the preponderance of evidence does not support Applicant’s allegation that the claimed strains are non-naturally occurring. Furthermore, there is no evidence that the mother strains of claim 9 are not naturally occurring such that any mutant strain made from said mother strains might not be natural products.
It is noted that Applicant did not provide any arguments traversing the separate written description of record under 35 U.S.C. § 112(a), separate from the withdrawn new matter rejections of record and briefly summarized as regarding the claimed genus of bacteriophage-insensitive mutant strains of S. thermophilus and the lack of adequate descriptive support to a representative number of species and structure-function correlation in the original disclosure to support generic claim 9.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
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/Sean C. Barron/Primary Examiner, Art Unit 1653