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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 18, 2026 has been entered.
Claim Objections
Claim 33 is objected to because of the following informalities:
Claim 33 line 11 recites “growing the test cell in a yeast cell a media lacking serine;”. This appears to be a typo and likely intended to recite “growing the test cell in a yeast cell assay in or on a media lacking serine;”.
Appropriate correction is required.
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 1-3, 5, 7-13, 15, 16, 33, 36-38, and 63-65 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception without significantly more. Claims 1, 16, and 33 recite methods of screening a subject for a serine deficiency, determining if a subject has a serine deficiency, or treating a subject with an amino acid deficiency comprising: isolating or obtaining genomic DNA from the subject, identifying or detecting the gene encoding PSAT, determining the subject has a variant of the gene of interest, inserting the variant of the gene into a construct, introducing the construct into a test cell, growing the test cell in a media lacking serine, analyzing or evaluating growth of the test cell compared to growth of a control cell, storing the quantified growth information in a look up table, determining the subject has a deficiency when the test cell growth is lower than the control cell control, and, in claim 33 only, providing an adequate amount of an amino acid supplement.
These claims recite two judicial exceptions: 1. Abstract idea and 2. Natural phenomenon. The “identifying” and “determining” steps are mental processes or steps completed in the mind and, thus, are abstract ideas. The relationship between reduced growth of the test cell comprising the gene variant and the presence of disease recite a natural phenomenon.
These judicial exceptions are not integrated into a practical application because the steps of isolating or obtaining genomic DNA from the subject, detecting the gene encoding PSAT, inserting the variant of the gene into a construct, introducing the construct into a test cell, growing the test cell in a media lacking serine, analyzing or evaluating growth of the test cell compared to growth of a control cell, are storing the quantified growth information in a look up table are extra-solution activities. Claim 33 recites providing an adequate amount of an amino acid supplement, but this treatment is not particular; see MPEP 2106.04(d)(2)a. The claims recite the gene encoding PSAT, of importance in serine biosynthesis. Claim 34 recites the amino acid supplement is serine, and this treatment is particular – claim 34 is not included in this rejection. Claims 2, 3, 5, 7-13, 15, 36-38, and 63-65 do not recite additional steps, but rather further limit step the steps, the amino acid deficiency disorder, or the contents of the look up table recited in claims 1, 16, or 33.
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because isolating or obtaining genomic DNA from the subject, detecting the gene encoding PSAT, inserting the variant of the gene into a construct, introducing the construct into a test cell, growing the test cell in a media lacking serine, analyzing or evaluating growth of the test cell compared to growth of a control cell, are storing the quantified growth information in a look up table are insignificant extra-solution activities. More specifically, isolating or obtaining genomic DNA from the subject, detecting the gene encoding PSAT, inserting the variant of the gene into a construct, introducing the construct into a test cell, growing the test cell in a media lacking an amino acid, analyzing or evaluating growth of the test cell compared to growth of a control cell; are well-known, routine, and conventional activities; 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), Trevisson et al. (Human Mutation. 28(7): 694-702; Published: Feb 26, 2007), Guzman et al. (PLOS ONE. 9(3): e92444: Published: Mar 19, 2014), Mukherjee et al. (Fungal and Parasitic Infections. 71(8): 4333-4340: Published: August 1, 2003), Bray et al. (Current Protocols in Molecular Biology. 109: 14.17.1-14.17.13; Published: January 2015), DeKoning et al. (Lancet. 364: 2221-2222; Published: December, 2004), Starita et al. (The American Journal of Human Genetics. 101: 315-325; September 7, 2017), and Sun et al. (Genome Research. 26: 670-680; Published: March 14, 2016).
Thus, claims 1-3, 5, 7-13, 15, 16, 33, 36-38, and 63-65 recite judicial exceptions without integration into a practical application, and without significantly more.
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 1-3, 5, 7-13, 15, 34, 36-38, and 63-65 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 determining that a subject has a serine deficiency disease, a serine deficiency, or a serine deficiency disorder when the quantified growth of the test cell with the variant is lower than the quantified growth of the control cell. The term “lower” in claims 1, 16, and 33 is a relative term which renders the claim indefinite. The term “lower” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. More specifically, it is unclear to what degree lower the quantified growth of the test cell must be relative to the control cell in order to be determined to have a serine deficiency disease, a serine deficiency, or a serine deficiency disorder. Is quantified growth of the test cell at 98% of the control cell indicative of “determining the subject has” a serine deficiency disease, a serine deficiency, or a serine deficiency disorder?
For example, instant Figure 7 (reproduced below) demonstrates lower growth of test cells associated with “carrier parents” (the two middle columns) relative to the growth of the control cell (left most column), yet only the individual associated with the rightmost column is indicated as being “affected” by the deficiency, disease, or disorder. This figure indicates that growth marginally lower than the control is not indicative of disease, deficiency, or disorder, but rather there exists a critical degree of lower growth necessary to achieve this determination. That critical degree of lower growth is unclear.
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Thus, it is unclear to what degree lower must the growth must be in order to be determined to have the disease, deficiency, or disorder.
Claims 2, 3, 5, 7-9, 11-13, 15, 34, 36-38, and 63-65 are rejected for depending from claims 1, 16, or 33 and failing to remedy the indefiniteness. Claim 10 is not rejected here as it provides a percent of reduced growth which is indicated as lower.
Claims 1, 16, and 33 recite a step of evaluating the test cell for growth by quantifying growth in a yeast cell assay. In the preceding steps of providing a test cell and inserting the construct into the test cell, the test cell is not specified as being a yeast cell. It is unclear if the test cell is required to be a yeast cell.
Claims 2, 5, 7-13, 15, 34, 36-38, and 63-65 are rejected for depending from claims 1, 16, or 33 and failing to remedy the indefiniteness. Claim 3 is not rejected here as it recites that the test cell and control cell are yeast cells.
Claim 33 (a) recites identifying a subject or a carrier of an amino acid deficiency disorder and recites steps specific to the subject – not the carrier. Claim 33 the determining step recites how it is determined that a subject has the amino acid deficiency disorder. It is unclear how one identifies a carrier. Further, the preamble recites treating the subject and the providing step recites providing a supplement to the subject. If one were to somehow identify a carrier, would one still need to provide an amino acid supplement to the carrier? It is unclear how to perform the claimed method for a carrier.
Claims 34, 36-38, and 65 are rejected for depending from claim 33 and failing to remedy the indefiniteness.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 9 and 36 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 9 depends from claim 1. Claim 1 recites in the evaluating step and the final determining step “when quantified growth of the test cell is lower than quantified growth of the control cell”. Claim 9 recites “when quantified growth of the test cell is comparable to quantified growth of the control cell”. This outcome of comparable quantified growth is not encompassed in claim 1. Therefore, claim 9 further expands and fails to limit claim 1.
Claim 36 depends from claim 33 which recites that the subject is provided the amino acid supplement. Claim 36 recites that the fetus is the subject and that “the mother of the fetus is provided” the amino acid supplement. Because claim 36 states that the amino acid is provided to the mother of the fetus and the fetus is the subject and claim 33 states that the amino acid supplement is provided to the subject, claim 36 further expands and fails to limit claim 33.
This could be remedied by amending the claims to recite that the amino acid supplement is provided to the fetus by administration to the mother.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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 1-3, 5, 7-10, 15, 16, 33, 34, 36-38, and 63-65 are rejected under 35 U.S.C. 103 as being unpatentable over De Koning (Journal of Inherited Metabolic Disease. 40(4): 609-620; Published: June 26, 2017), in view of Melcher et al. (Current Genetics. 27: 501-508; Published: May 1995), Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009), Lee et al. (ACS Synthetic Biology. 4(9): 975-986; Published: Apr 14, 2015), Guzman et al. (PLoS ONE 9(3): e92444; Published: March 19, 2014), and Sun et al. (Genome Research. 26:670-680; Published: March 14, 2016).
Regarding PSAT in claims 1, 16, and 33, De Koning teaches that serine synthesis involves three enzymes, including PSAT, and that defects in the genes encoding any one of the three enzymes are associated with serine deficiency disorders; see page 610. Regarding claims 15 and 38, one disease associated with serine deficiency is Neu-Laxova syndrome (NLS); see page 610. Regarding life stage of the subject in claim 2, De Koning teaches that NLS is associated with intrauterine or early postnatal death and that most children with serine deficiency suffer from the infantile phenotype; see page 610.
While De Koning teaches the need for further development of functional assays to diagnose amino acid disorders (see the last paragraph), the reference does not teach the methodology of a functional assay.
Regarding claims 1, 3, 16, and 33, Trevisson et al. teaches the identification of novel mutations of the ASL gene in patients diagnosed with argininosuccinic aciduria, a genetic disorder caused by a deficiency of the enzyme argininosuccinate lyase (ASL), which is responsible for arginine biosynthesis, by isolating genomic DNA from a patient via peripheral blood leukocytes, detecting the gene for the ASL gene, inserting variants or site-specific mutants of human ASL into an expression vector which is introduced into yeast mutant lacking ARG4, and growing said yeast in synthetic minimal medium which does not contain amino acids and comparing the growth of the genetically edited test cell to that of a control; see Experimental Procedures. Trevisson et al. demonstrates reduced growth of the test cell compared to the control. ASL is an enzyme responsible for arginine biosynthesis and no growth or reduced growth of cells with mutant ASL on media lacking arginine suggests that the resulting ASL enzyme is a non-functional protein or a protein with decreased function. Regarding claim 37, Trevisson et al. teaches using control cells having either wild type or truncated alleles of ARG4; see Figure 2 “WT” and “DEL”.
Regarding the number of hours for cell growth in claim 8, Trevisson et al. that the transformed yeast was grown on plates containing solid media for 3 days or 72 hours; see page 28928 right column second to last paragraph.
Regarding claims 9 and 10, the claims simply require that the growth of the test cell be compared to the growth of the control. For claim 9, if the growth of the cells is comparable, then the growth of the test cells would be at least 90% that of the liquid media containing control cells. For claim 10, if the growth of the test cells is lower than the control, then the growth of the test cells would be 79% or less than that of the control cells. Neither claims 9 nor 10 require performing any additional steps. Figure 2 of Trevisson et al. shows the growth of yeast transformed with mutant human ASL compared to wild type human ASL. Most the mutants assessed, especially those in the left image, if grown in liquid media with optical density was measured, the optical density would be less than 80% that of the wild type control. Conversely, mutants V335L and V178M, appear to show comparable growth to that of the wild type control and if grown in liquid media with optical density was measured, the optical density may be within 10% that of the control.
Neither De Koning nor Trevisson et al. teach a linear DNA construct, evaluating cell growth in a media by quantifying growth, nor storing quantified growth information in a look up table.
Regarding the linear DNA constructs of claims 1 and 33, the instant disclosure states that the construct is a "linear” DNA molecule (double or single stranded) that can be integrated into the yeast nuclear or mitochondrial genome by homologous recombination; see paragraph 0050.
Lee et al. teaches that compared to plasmid transformations, chromosomal integration into yeast DNA has been difficult with significantly lower efficiency; see page G left column second paragraph. When using a cutter plasmid linearized with restriction digest prior to transformation in the Cas9 and I-SceI integration systems, the authors found improved integration efficiency with low off-target integration; see last paragraph on page G. In comparison to plasmid transfection, the use of a linearized cutter plasmid in the I-SceI system resulted in increased efficiency that was 1.8-fold that of plasmid transformation; see Figure 8.
Further, neither De Koning, Trevisson et al. nor Lee et al. teach evaluating cell growth in a media by quantifying growth nor storing quantified growth information in a look up table.
Regarding measuring cell growth in claims 1 and 7, Trevisson et al. teaches those serial dilutions of the transformed yeast were plated on synthetic minimal medium plates lacking both uracil and arginine and growth was assessed by the relative quantity of colonies on solid media compared to a wild type control; see page 28928 left column last paragraph. However, the assessment of growth by Trevission et al. is qualitative rather than quantitative.
Guzman et al. teaches using an ImageJ Plugin to quantify cell growth on a solid media by taking a picture of the solid media, converting the image to greyscale, and having the software quantify the cell growth corresponding to the number of pixels in a selected area.
Neither De Koning, Trevisson et al., Lee et al. nor Guzman et al. teach storing quantified growth information in a look up table.
Sun et al. teaches using yeast complementation assays to the functional phenotype of variants potentially associated with human disease. Regarding the look up table of claims 1, 16, and 33 recited to comprise quantified growth information, Sun et al. teaches storing the quantified growth information of variants in a table; see Supplemental Table S4. Regarding claims 63-65, Sun et al. teaches calculating FCS and FCT scores based on the relative loss of function measured by growth as compared to the wild-type control. Sun et al. teaches a table comprising these FCS and FCT scores, based on the quantified growth information, and the clinical significance (eg. Pathogenic); see Supplemental Table S3. Regarding the final wherein clause of claims 1, 16, and 33, which recites “wherein the quantified growth of the test cell with the variant in the yeast cell assay establishes a test cell growth threshold for predicting the disease”, simply establishes an intended use of the quantified growth of the test cell in another unrecited process of predicting disease and does not require. However, in the interest of compact prosecution, Sun et al. teaches using the quantified growth of the test cell to establish a threshold for predicting disease by using the growth of the test cell to assign a FCS score and developing a pathogenic threshold FCS score; see pages 672 and 678, for example.
Given that De Koning teaches that serine deficiency diseases or disorders are caused by genetic defects in the genes encoding enzymes responsible for serine biosynthesis, including phosphoserine aminotransferase (PSAT), Melcher et al. teaches that the SER1 gene in yeast encodes phosphoserine aminotransferase which catalyzes the formation of phosphoserine from 3-phosphohydroxy-pyruvate, and Trevisson et al. teaches a yeast functional assay for screening for another amino acid deficiency comprising knocking out endogenous yeast ARG4 and inserting variants of human ASL to assess enzyme function, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method taught by Trevisson et al. knocking out SER1 and inserting PSAT1 to assess the function of PSAT by yeast growth on a serine deficient media. One would have been motivated to make this modification by De Koning which teaches the need for functional assays to diagnose amino acid deficiency diseases or disorders and Melchor et al. which teaches the similar function of SER1 in yeast as PSAT1 in humans.
Moreover, given the improved integration efficiency and low incidence of off-target integration, it would have been obvious to modify the functional complementation assay taught by Trevission et al. for screening a subject for an amino acid deficiency disorder such that the yeast homologous gene knock down could be paired with guided chromosomal integration of a linearized plasmid comprising the gene of interest as taught by Lee et al. With the improved efficiency and low off-target integrations of the method taught by Lee et al., one would have a reasonable expectation of success and predictable results.
Given that the method of using software to quantify cell growth was established in the art at the time of the effective filing date, it would have been obvious to add this method of automated image analysis as taught by Guzman et al. to the functional complementation assay taught by Trevission et al. and modified by the linear construct integration taught by Lee et al. in order to provide a quantifiable metric to compare cell growth. Doing so would provide a metric with which one could perform quantitative statistics to determine if differential growth was significant.
Regarding the age or life stage of subjects to be screened for disease, it would have been obvious to screen subject who are neonatal given that De Koning teaches that most children with serine deficiency suffer from the infantile phenotype. One of ordinary skill in the art would have a reasonable expectation of using the method taught by Trevisson et al. to screen neonates because, like serine deficiency, argininosuccinic aciduria, the disease being screened in Trevisson et al., is commonly diagnosed in infancy or childhood. Regarding claim 5 wherein the subject is pregnant, given that serine deficiency onset can occur in adulthood and can be lethal as taught by De Koning, it would have been obvious to one of ordinary skill in the art to screen a patient for the serine deficiency disease when that suspected regardless of pregnancy status.
Moreover, regarding the step of providing an adequate amount of an amino acid supplement to the subject identified as having an amino acid deficiency in claims 33 and 34 or administering an amino acid supplement to the fetus by administration to the mother in claim 36, it would have been obvious to treat the subject with supplementation of the amino acid of which that subject cannot effectively produce through normal biosynthesis, and in an amount adequate to treat the deficiency, given that amino acids are required for protein synthesis and necessary for growth and development. Indeed, De Koning teaches that serine supplementation has been reported to successfully treat patients with infantile, juvenile and adult phenotypes of serine deficiency and that serine supplementation can be given antenatal; see page 611. Thus, one of ordinary skill in the art would have a reasonable expectation of success to treat serine deficiency disorders with serine supplementation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over De Koning (Journal of Inherited Metabolic Disease. 40(4): 609-620; Published: June 26, 2017), in view of Melcher et al. (Current Genetics. 27: 501-508; Published: May 1995), Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009), Lee et al. (ACS Synthetic Biology. 4(9): 975-986; Published: Apr 14, 2015), Guzman et al. (PLoS ONE 9(3): e92444; Published: March 19, 2014), and Sun et al. (Genome Research. 26:670-680; Published: March 14, 2016) as applied to claim(s) 1-3, 7-10, 15, 16, 33, 34, 36-38, and 63-65 above, and further in view of Acuna-Hidalgo et al. (The American Journal of Human Genetics. 95: 285-293; Published: September 4, 2014).
The teachings of De Koning, in view of Melcher et al., Trevisson et al., Lee et al., Guzman et al., and Sun et al. as applied to claim(s) 1-3, 7-10, 15, 16, 33, 34, 36-38, and 63-65, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach a method where the gene of interest is a single-nucleotide polymorphism (SNP).
Acuna-Hidalgo et al. teaches NLS caused by a c.296C>T mutation in the PSAT1 gene; see page 286 for example.
Given that the serine deficiency disease, NLS, has been found in a patient with a C>T single nucleotide mutation, or a SNP, it would have been obvious to one of ordinary skill in the art to further analyzed the PSAT1 variant for SNPs in order to compile a list of SNPs associated with non-functional PSAT and serine deficiency as in Table 1 of Acuna-Hidalgo et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over De Koning (Journal of Inherited Metabolic Disease. 40(4): 609-620; Published: June 26, 2017), in view of Melcher et al. (Current Genetics. 27: 501-508; Published: May 1995), Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009), Lee et al. (ACS Synthetic Biology. 4(9): 975-986; Published: Apr 14, 2015), Guzman et al. (PLoS ONE 9(3): e92444; Published: March 19, 2014), and Sun et al. (Genome Research. 26:670-680; Published: March 14, 2016) as applied to claim(s) 1-3, 7-10, 15, 16, 33, 34, 36-38, and 63-65 above, and further in view of McDonald (Handbook of Biological Statistics. 2nd Edition. University of Delaware; Published: 2009).
The teachings of De Koning, in view of Melcher et al., Trevisson et al., Lee et al., Guzman et al., and Sun et al. as applied to claim(s) 1-3, 7-10, 15, 16, 33, 34, 36-38, and 63-65, from which these claims depend are given previously in this Office action and are fully incorporated here.
The references do not teach a method where a t-test is performed to determine if the difference in cell growth is significant.
Regarding the t-test of claim 13, McDonald teaches using a t-test when performing statistical analysis of in the instance of one nominal variable and one measurement variable; see page 118. In the instant case, the nominal variable is the gene of interest from a subject vs. the wild type gene of interest and the measurement variable is cell growth over time for each group.
Thus, it would have been obvious to one of ordinary skill in the art to perform a t-test following the modified functional complementation assay taught by De Koning in view of Melcher et al., Trevisson et al. and Lee et al. and the image analysis for cell growth as taught by Guzman et al. in order to compare the growth of the test cells to the growth of the control cells because a t-test is what is performed when comparing one metric between two populations. Further, it would have been obvious that a statistically significant reduction in growth as examined by t-test would indicate that the mutation resulted in a non-functional protein or one with decreased function.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5, 7-13, 15, 16, 33, 34, 36-38, and 63-65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15, 31, 43-48, 54-58, 70-72, 75-80 of copending Application No. 17/768104 (reference application) in view of De Koning (Journal of Inherited Metabolic Disease. 40(4): 609-620; Published: June 26, 2017), Melcher et al. (Current Genetics. 27: 501-508; Published: May 1995), Trevisson et al. (The Journal of Biological Chemistry. 284(42): 28926-28934; Published: Oct 16, 2009), and Sun et al. (Genome Research. 26:670-680; Published: March 14, 2016).
Regarding instant claims 1, 16, and 33, the copending claims are drawn to methods of screening a subject for disease, determining an amino acid deficiency and treating a subject with amino acid deficiency. Similar to the methods of instant claims 1, 16, and 33, copending claims 1-15, 31, 43-48, 54-58, 70-72, 75-80 teach methods comprising obtaining DNA from a subject, identifying a gene of interest, inserting the gene into a construct, providing a test cell wherein the homologous gene has been knocked out, introducing the construct into the test cell, evaluating test cell growth in a media lacking an amino acid and comparing test cell growth to a control cell that has the homologous gene wherein slow growth indicates a non-functional protein or protein with decreased function, and generating a look up table.
Regarding the age of the subject in instant claim 2, copending claim 2 teaches that the subject is a fetus, neonate, juvenile, or adult.
Regarding instant claim 3, copending claim 3 teaches that the test and control cells are yeast.
Regarding instant claim 5, copending claim 5 teaches that the subject is pregnant.
Regarding instant claim 7, copending claim 7 teaches measuring growth by number of pixels.
Regarding instant claim 8, copending claim 8 teaches the same time intervals.
Regarding instant claims 9 and 10, copending claims 9 and 10 teach the same relative percent growth.
Regarding instant claims 11-13, copending claims 11-13 teach analyzing for a SNP associated with a non-functional or reduce function protein and performing a T-test to compare growth of the test cell to growth of the control cell.
Regarding instant claims 15 and 38, copending claim 15 teach the disease is an amino acid deficiency, NLS, or retinal neuropathy.
The claims of copending Application No. 17/768104 does not teach applying these methods where serine is the amino acid lacking from the growth media or where PSAT1 is the gene, nor do the copending claims teach providing an amino acid supplement.
Regarding PSAT in claims 1, 16, and 33, De Koning teaches that serine synthesis involves three enzymes, including PSAT, and that defects in the genes encoding any one of the three enzymes are associated with serine deficiency disorders; see page 610. Regarding claims 15 and 38, one disease associated with serine deficiency is Neu-Laxova syndrome (NLS); see page 610. Regarding life stage of the subject in claim 2, De Koning teaches that NLS is associated with intrauterine or early postnatal death and that most children with serine deficiency suffer from the infantile phenotype; see page 610.
De Koning does not teach comparing to a second control cell.
Regarding instant claims 1, 3, 16, and 33, Trevisson et al. teaches the identification of novel mutations of the ASL gene in patients diagnosed with argininosuccinic aciduria, a genetic disorder caused by a deficiency of the enzyme argininosuccinate lyase (ASL), which is responsible for arginine biosynthesis, by isolating genomic DNA from a patient via peripheral blood leukocytes, detecting the gene for the ASL gene, inserting variants or site-specific mutants of human ASL into an expression vector which is introduced into yeast mutant lacking ARG4, and growing said yeast in synthetic minimal medium which does not contain amino acids and comparing the growth of the genetically edited test cell to that of a control; see Experimental Procedures. Trevisson et al. demonstrates reduced growth of the test cell compared to the control. ASL is an enzyme responsible for arginine biosynthesis and no growth or reduced growth of cells with mutant ASL on media lacking arginine suggests that the resulting ASL enzyme is a non-functional protein or a protein with decreased function. Regarding instant claim 37, Trevisson et al. teaches using control cells having either wild type or truncated alleles of ARG4; see Figure 2 “WT” and “DEL”.
Neither the copending claims, De Koning, nor Trevisson et al. teach storing quantified growth information in a look up table.
Sun et al. teaches using yeast complementation assays to the functional phenotype of variants potentially associated with human disease. Regarding the look up table of instant claims 1, 16, and 33 recited to comprise quantified growth information, Sun et al. teaches storing the quantified growth information of variants in a table; see Supplemental Table S4. Regarding instant claims 63-65, Sun et al. teaches calculating FCS and FCT scores based on the relative loss of function measured by growth as compared to the wild-type control. Sun et al. teaches a table comprising these FCS and FCT scores, based on the quantified growth information, and the clinical significance (eg. Pathogenic); see Supplemental Table S3. Regarding the final wherein clause of instant claims 1, 16, and 33, which recites “wherein the quantified growth of the test cell with the variant in the yeast cell assay establishes a test cell growth threshold for predicting the disease”, simply establishes an intended use of the quantified growth of the test cell in another unrecited process of predicting disease and does not require. However, in the interest of compact prosecution, Sun et al. teaches using the quantified growth of the test cell to establish a threshold for predicting disease by using the growth of the test cell to assign a FCS score and developing a pathogenic threshold FCS score; see pages 672 and 678, for example.
Given that De Koning teaches that serine deficiency diseases or disorders are caused by genetic defects in the genes encoding enzymes responsible for serine biosynthesis, including phosphoserine aminotransferase (PSAT), Melcher et al. teaches that the SER1 gene in yeast encodes phosphoserine aminotransferase which catalyzes the formation of phosphoserine from 3-phosphohydroxy-pyruvate, and the copending claims and Trevisson et al. teaches a yeast functional assay for screening for another amino acid deficiency comprising knocking out an endogenous yeast and inserting variants of the human homolog to assess enzyme function, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to modify the method taught by copending claims and Trevisson et al. knocking out SER1 and inserting PSAT1 to assess the function of PSAT by yeast growth on a serine deficient media. One would have been motivated to make this modification by De Koning which teaches the need for functional assays to diagnose amino acid deficiency diseases or disorders and Melchor et al. which teaches the similar function of SER1 in yeast as PSAT1 in humans.
Regarding the age or life stage of subjects to be screened for disease, it would have been obvious to screen subject who are neonatal given that De Koning teaches that most children with serine deficiency suffer from the infantile phenotype. One of ordinary skill in the art would have a reasonable expectation of using the method taught by the copending claims and Trevisson et al. to screen neonates because, like serine deficiency, argininosuccinic aciduria, the disease being screened in Trevisson et al. , is commonly diagnosed in infancy or childhood and the copending claims teach using the methods in subjects of these life stages. Regarding instant claim 5 wherein the subject is pregnant, given that serine deficiency onset can occur in adulthood and can be lethal as taught by De Koning, it would have been obvious to screen a patient for the serine deficiency disease when that suspected regardless of pregnancy status. Further, one would have had a reasonable expectation of success because the copending claims teach using a similar method of screening for amino acid deficiency in pregnant subjects.
Moreover, regarding the step of providing an adequate amount of an amino acid supplement to the subject identified as having an amino acid deficiency in instant claims 33 and 34 or administering an amino acid supplement to the fetus by administration to the mother in instant claim 36, it would have been obvious to treat the subject with supplementation of the amino acid of which that subject cannot effectively produce through normal biosynthesis, and in an amount adequate to treat the deficiency, given that amino acids are required for protein synthesis and necessary for growth and development. Indeed, De Koning teaches that serine supplementation has been reported to successfully treat patients with infantile, juvenile and adult phenotypes of serine deficiency and that serine supplementation can be given antenatal; see page 611. Thus, one of ordinary skill in the art would have a reasonable expectation of success to treat serine deficiency disorders with serine supplementation.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed March 18, 2026 are acknowledged. All remaining previous rejections were overcome by amendment to the claims. New rejections are set forth to address the amended claims.
Conclusion
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1644
/JULIET C SWITZER/Primary Examiner, Art Unit 1682
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