DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Objections
Claims 1 and 33 are objected to because of the following informalities:
Claim 1 line 13 recites “wherein a growth of the test cell growth is compared to a growth of a control cell”. The second “growth” should be deleted.
Claim 33 line 23 should end with a semi-colon.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 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.
Claims 1-13, 15, 16, and 33-38 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 16, and 33 recite many steps and between the final two steps recited there is not “and” or “or”. It is unclear is all of the recited steps must be completed or just a single step must be completed. Claim 33 line 12 recites “and” between the 5th and 6th sub-step recited which makes more unclear which steps are required to be completed. For the purpose of compact prosecution, the claims are interpreted as requiring all steps recited.
Claims 2-13, 15, and 34-38 are rejected for depending from claims 1, 16, and 33 and failing to remedy the indefiniteness.
Claim 16 recites the limitation "the amino acid deficiency disorder" in lines 24-26. There is insufficient antecedent basis for this limitation in the claim. Specifically, the claim lacks antecedent basis for the word “disorder”. Similarly, claim 38 recites "the amino acid deficiency disorder". Claim 33, from which claim 38 depends, does not provide basis for this limitation – specifically, the word “disorder”.
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 1-13, 15, 16, and 33-38 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.
This is a new matter rejection.
Claims 1, 16, and 33 have been amended to recite two new steps:
comparing quantified growth of the test cell with quantified growth information recorded in a look up table of other variants previously established using the yeast cell assay, wherein the look up table provides a predicted threshold of correlation between quantified growth of the other variants in the yeast cell assay and [the disease / the amino acid deficiency disorder / the amino acid deficiency];
identifying the subject as having [the disease / the amino acid deficiency disorder / the amino acid deficiency] when quantified growth of the test cell with the variant in the yeast cell assay is comparable to or lower than the predicted threshold.
Applicant states that support for the amendments can be found in paragraphs 0020, 0025, 0026, 0057, 0072, and 0084.
The instant Specification does not provide adequate support because while the Specification refers to a look up table (see paragraphs 0020-0023, 0026, 0057, 0072-0074, 0101) and predicted threshold (see paragraph 0057), the Specification does not teach that:
1. The growth of the test cell can be compared to the growth of other variants recorded in a look up table.
The only comparison of that is taught in the instant Specification is the comparison of the growth of the test cell and the growth of the control cell. There is no teaching in the instant disclosure to support that a comparison of test cell growth could be made to the look up table.
2. The predicted threshold is a correlation between quantified growth of other variants in the yeast cell assay and the disease, amino acid deficiency disorder, or amino acid deficiency.
Paragraph 0057 merely states that the look up table provides “predicted thresholds for determining the function of the protein”. Of correlations, paragraph 0072 states that the look up table can comprise a correlation between allelic data for a least one protein and a particular trait or phenotype, such as a particular disease. The Specification provides no definition for allelic data, but one of ordinary skill in the art would understand this to mean DNA sequences of alleles or population frequency statistics. In fact, paragraph 0023 supports this interpretation by stating that the look up table comprises genetic mutations or combinations of genes indicative of disease.
3. The predicted threshold can be used to identify a subject as having the disease, amino acid deficiency disorder, or amino acid deficiency.
The sole mention of a predicted threshold in Paragraph 0057 merely states that the look up table provides “predicted thresholds for determining the function of the protein”. There is no teaching of identifying a subject based off a comparison to the predicted threshold.
Additionally, the instant disclosure does not teach which “other variants” are appropriate for comparison of growth data nor how to calculate the predicted threshold.
Thus, one of ordinary skill in the art would not conclude based on the instant Specification that Applicant was in possession of a method comprising the steps of comparing and identifying as recited in claims 1, 16, and 33.
Claims 1-13, 15, 16, and 33-38 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claims 1, 16, and 33 have been amended to recite two new steps:
comparing quantified growth of the test cell with quantified growth information recorded in a look up table of other variants previously established using the yeast cell assay, wherein the look up table provides a predicted threshold of correlation between quantified growth of the other variants in the yeast cell assay and [the disease / the amino acid deficiency disorder / the amino acid deficiency];
identifying the subject as having [the disease / the amino acid deficiency disorder / the amino acid deficiency] when quantified growth of the test cell with the variant in the yeast cell assay is comparable to or lower than the predicted threshold.
The claims are drawn to methods of determining or screening for any disease associated with an amino acid deficiency, an amino acid deficiency disorder, or an amino acid deficiency by yeast functional assay assessing any gene of interest (in claim 16) or any gene encoding an enzyme of an amino acid synthesis pathway (in claims 1 and 33).
The nature of the invention is that genetic variants associated with disease associated with an amino acid deficiency, an amino acid deficiency disorder, or an amino acid deficiency can be identified by yeast complementation or functional assay, wherein the variant suspected to be associated with disease or deficiency is inserted into a test yeast cell replacing the homologous yeast gene. The test cell is then grown on media lacking a particular amino acid and the resulting growth is compared to the growth of a yeast, in which the gene homologous to the gene of interest remains intact. Previously, the method taught that lower test cell growth comparted to control cell growth was indicative of disease or deficiency. As amended, the invention now further requires comparison to a look up table comprising growth from functional assays of other, undisclosed variants and identifying a subject having a disease or deficiency based on the comparison to a predicted threshold.
The prior art teaches amino acid deficiencies, including serine deficiency, and teaches that DNA-based diagnostics are replacing the biochemical enzyme-based diagnostic; see De Koning et al. (Journal of Inherited Metabolic Disease. 40: 609-620; Published: Jun 26, 2017), Trevisson et al. (Human Mutation. 28(7): 694-702; Published: Feb 26, 2007), and Erez et al. (AJMG Part C: Seminars in Medical Genetics. 157(1): 45-53; Published: Feb 15, 2011). Additionally, the art teaches using yeast complementation assays to identifying patients with amino acid deficiencies; see Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009), Kruger and Cox. (Human Molecular Genetics. 4(7): 1155-1161; Published: Jul 1995), and Hamza et al. (Genetics. 201:1263-1274; Published: Sep 9, 2015). Additionally, ClinVar provides a tool similar to the look up table as taught in the instant Disclosure; see paragraph 0072 and the Clin Var PSAT1 Gene Inquiry. (National Library of Medicine, National Center for Biotechnology Information; Entry: June 28, 2015).
While the level of skill in the art is high, the level of unpredictability is also high. Claims 1, 16 and 33 recite comparing growth of the test cell to growth information of other variants previously established using the yeast cell assay and recorded in the look up table, wherein the look up table provides a predicted threshold of correlation between the growth of other variants and the disease, the amino acid deficiency disorder, or the amino acid deficiency. Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009) demonstrated that yeast expressing different variants of ASL, a gene needed for arginine synthesis, have varying degrees of growth in the yeast complementation assay using arginine-deficient media. As evidenced by Figure 4 of Marchesani et al. (Biomolecules. 13(8): 1219: Published: August 4, 2023) pathogenic variants of the gene PSAT1, needed for serine synthesis, demonstrate varying degrees of enzymatic activity. One of ordinary skill in the art would expect that variants of the PSAT1, having varying degrees of activity, would display varying degrees of growth on a serine-free media. Since the predicted threshold is recited as a correlation of which one of the variable is growth, one would expect that it would vary unpredictably based on the gene of interest or combinations of genes of interest and based on the other variants previously assessed by growth.
Similarly, the second variable in the correlation that is the predicted threshold is the disease, the amino acid deficiency disorder, or the amino acid deficiency. Again, this predicted threshold is recited to be based off the growth of other variants in the yeast cell assay assessed previously. In the claimed methods, identifying the disease, the amino acid deficiency disorder, or the amino acid deficiency is accomplished by comparing the growth of the test cell with a predicted threshold. Since the predicted threshold is needed to identify the disease, the amino acid deficiency disorder, or the amino acid deficiency in the yeast cell assay and identifying the disease, the amino acid deficiency disorder, or the amino acid deficiency is critical for establishing the predicted threshold, the predicted threshold is entirely unpredictable.
The amount of direction provided regarding making or using the predicted thresholds is minimal. The instant disclosure mentions predicted thresholds only a single time stating that they are provided on the look up table. There is no exemplary look up table with predicted threshold provided in the instant disclosure. The guidance for making the look up table is minimal (see paragraph 0101) and it lacks direction for calculating the predicted threshold. Further, there is no working example which exemplifies the steps of comparing growth of the test cell to the look up table nor identifying a subject as having the disease, the amino acid deficiency disorder, or the amino acid deficiency based on a comparison to a predicted threshold.
In order to use the claimed invention, one would have to first generate a look up table and establish a predicted threshold. To generate a look up table, one would have to assess the growth by yeast cell assay of a large assortment of variants for each gene of interest. These variants would have to be from patients who have already been diagnosed with the disease, the amino acid deficiency disorder, or the amino acid deficiency by some other means in order to establish a predicted threshold as recited in the claims. Then, one would need to optimize the predicted threshold accounting for a reasonable margin of error. This process would need to be repeated for every gene of interest and every combination of alleles of genes of interest as taught in instant paragraph 0057. For the three genes recited in claims 6 and 35, this would be a huge experimental undertaking. The scope of claims 1, 16, and 33 is far broader than the three genes of claims 6 and 35 and encompass any gene associated with a disease associated with amino acid deficiency or associated with an amino acid deficiency or amino acid deficiency disorder. The amount of experimentation to practice the claimed methods in line with the claimed scope is enormous.
Considering the unpredictability, the high level of skill, the lack of Applicant-provide guidance and working examples, it would take more than a reasonable amount of experimentation to make or use the invention commensurate in scope with the claims.
Response to Arguments
Applicant’s amendments filed June 9, 2025 are acknowledged. All remaining previous rejections were overcome by amendment to the claims. New rejections are set forth to address the amended claims.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KATHERINE ANN HOLTZMAN whose telephone number is (571)270-0252. The examiner can normally be reached Monday - Friday 7:30am - 5:00pm.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1644
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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