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 .
Status of the Claims
Claims 1-3, 5-7, and 9-22 are pending and examined herein.
Claims 4, 8, and 23 are canceled.
Priority
As detailed on the 14 November 2022 filing receipt, the application claims priority as early as 22 October 2019, to foreign application AU 2019903966. At this point in examination, all claims have been interpreted as being accorded this priority date as the effective filing date.
Information Disclosure Statement
The information disclosure statements (IDS) were submitted on 20 April 2022 and 16 November 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the references are being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. Example of hyperlinks or browser-executable code occurs at multiple places in the specification (pg. 19, line 30; pg. 23, second paragraph; pg. 24, line 7; pg. 25, line 28; pg. 29, line 34. See MPEP § 608.01.
The disclosure is objected to because “aneuploidies” is misspelled as “aneuplodies” (pg.22, line 15).
Appropriate correction is required.
Claim Objections
Claim 19 is objected to because of the following informalities: the comma following “parent’s” is not required. 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 5-6 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.
Claim 5 recites two abbreviations – MPC and CADD – which are not defined within the claims, rendering them unclear. Explanation of these terms’ definitions may overcome this rejection.
Claim 5 recites an MPC score greater than “about 2” and a Phred score of greater than “about 20”. The term “about” 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. The specification discloses about refers to “+/-10%” or “more preferably +/- 5%” (pg. 8, lines 10-11).
Claim 6 is rejected on similar grounds as it recites a VAF threshold of “about 0.35.”
Claim 6 is also rejected because it recites a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation, which may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). The claim recites the broad range of 0.25 to 0.45, the narrower range of 0.3 to 0.4, and the narrower limitation of about 0.35. The claim is considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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, 9-22 are rejected under 35 USC § 101 because the claimed inventions are directed to an abstract idea without significantly more. "Claims directed to nothing more than abstract ideas (such as a mathematical formula or equation), natural phenomena, and laws of nature are not eligible for patent protection" (MPEP 2106.04 § I). Abstract ideas include mathematical concepts, and procedures for evaluating, analyzing or organizing information, which are a type of mental process (MPEP 2106.04(a)(2)). The claims as a whole, considering all claim elements individually and in combination, are directed to a judicial exception at Step 2A, Prong 2, and the additional elements of the claims, considered individually and in combination, do not provide significantly more at Step 2B than the abstract idea of screening an embryo for variations.
MPEP 2106 organizes JE analysis into Steps 1, 2A (Prong One & Prong Two), and 2B as analyzed below.
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter (MPEP 2106.03)?
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of
nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Step 1: Are the claims directed to a 101 process, machine, manufacture, or composition of matter (MPEP 2106.03)?
The claims are directed to methods, which falls within one of the categories of statutory subject matter. [Step 1: Yes]
Step 2A, Prong One: Do the claims recite a judicially recognized exception, i.e., a law of nature, a natural phenomenon, or an abstract idea (MPEP 2106.04(a-c))?
With respect to Step 2A, Prong One, the claims recite judicial exceptions in the form of abstract ideas. MPEP § 2106.04(a)(2) further explains that abstract ideas are defined as:
• mathematical concepts (mathematical formulas or equations, mathematical relationships
and mathematical calculations) (MPEP 2106.04(a)(2)(I));
• certain methods of organizing human activity (fundamental economic principles or practices, managing personal behavior or relationships or interactions between people) (MPEP 2106.04(a)(2)(II)); and/or
• mental processes (concepts practically performed in the human mind, including observations, evaluations, judgments, and opinions) (MPEP 2106.04(a)(2)(III)).
Mathematical concepts recited in the independent claims include filtering based on a variant allele frequency, where values are compared to a threshold (claims 1 and 22). Numerical comparisons are interpreted as a mathematical concept.
Mental processes, defined as concepts practically performed in the human mind such as steps of observing, evaluating, or judging information, recited in the independent claims include identifying variations (claims 1 and 22), comparing variations (claims 1 and 22), and filtering identified variations (claims 1 and 22). Identifying and comparing variations are interpreted as evaluating information to discover patterns, which the human mind is practically equipped to do. Filtering variations based on VAF can be interpreted as data evaluation in comparing two data values, which the human mind is practically equipped to do.
Dependent claims 2-3 recite using one or more pathogenicity prediction algorithms, which is interpreted as using math.
Dependent claim 5 recites scoring variation, which generating a score is interpreted as a mathematical concept.
Dependent claim 6 recites additional information about the VAF threshold and thus is interpreted as further information about the mathematical concept discussed above.
Dependent claim 7 recites further comparison to a database, where data comparison in a step the human mind is practically equipped to perform.
Dependent claims 9-10 recite further information about variations, which are related to the data analysis step and part of the mental processes abstract idea.
Hence, the claims explicitly recite numerous elements that, individually and in combination,
constitute abstract ideas. The claims must therefore be examined further to determine whether they
integrate that abstract idea into a practical application (MPEP 2106.04(d)). [Step 2A: Yes]
Step 2A, Prong Two: If the claims recite a judicial exception under Prong One, then is the judicial exception integrated into a practical application by an additional element (MPEP 2106.04(d))?
Elements in addition to the abstract ideas recited in the claims are: obtaining whole genome sequencing data (claims 1 and 22), aligning whole genome sequencing data to a reference genome (claims 1 and 22), culturing the embryo (claims 11 and 21), performing a biopsy on the embryo (claim 11), amplifying genomic DNA from the biopsy (claim 11), sequencing amplified genomic DNA (claim 11), trophectoderm biopsy (claim 12) that is performed within 5-6 days of culture (claim 13), multi-displacement amplification (claim 14), nanoball sequencing (claim 15) performed with combinatorial probe anchor ligation (claim 16), a reference genome being a Genome Reference Consortium Human Build (claim 17), screening two embryos (claim 18), transferring the embryo (claims 19 and 21), the embryo being human (claim 20), and fertilizing an embryo (claim 21).
These steps, aside from the transferring step, are steps required for generation of data for comparing variations in the child and parent genomes to determine if a trait – whether broadly phenotypic or more specifically pathogenic – is present. Therefore, these are data collection steps. Data collection steps are insignificant extra solution activity and do not integrate the abstract idea into a practical application (MPEP 2016.05(g)). The transferring step occurs after the abstract steps occur. The transferring step is broadly recited and does not appear to be directly impacted by the abstract screening steps. Therefore, this step is interpreted as mere instructions to apply the abstract idea, which does not integrate the abstract idea into a practical application. [Step 2A Prong Two: No]
Step 2B: Do the claims recite a non-conventional arrangement of elements in addition to any identified judicial exception(s) (MPEP 2106.05)?
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself. Step 2B of 101 analysis determines whether the claims contain additional elements that amount to an inventive concept, and an inventive concept cannot be furnished by an abstract idea itself (MPEP 2106.05).
Elements in addition to the abstract ideas recited in the claims are: obtaining whole genome sequencing data (claims 1 and 22), aligning whole genome sequencing data to a reference genome (claims 1 and 22), culturing the embryo (claims 11 and 21), performing a biopsy on the embryo (claim 11), amplifying genomic DNA from the biopsy (claim 11), sequencing amplified genomic DNA (claim 11), trophectoderm biopsy (claim 12) that is performed within 5-6 days of culture (claim 13), multi-displacement amplification (claim 14), and nanoball sequencing (claim 15) performed with combinatorial probe anchor ligation (claim 16), referring to a human genome (claim 17), screening two embryos (claim 18), transferring the embryo (claims 19 and 21), the embryo being human (claim 20), and fertilizing an embryo (claim 21).
The specification discloses “suitable methods for culturing, performing biopsies, amplifying DNA, and sequencing the DNA will be known by those skilled in the art” (pg. 4, lines 36-37). Multi-displacement amplification is disclosed in the specification as actively used in whole genome sequencing and thus considered to be conventional (pg. 13, lines 16-18).
Rubio (Biology of Reproduction 101(6): 1083-1090, 2019; newly cited) teaches at least trophectoderm biopsy for testing for genetic defects in embryos (abstract), including comparison to a reference sample and determining paternal and maternal origins (pg. 1084, col. 2, first paragraph). Culturing a blastocyst is taught (abstract), including in situations of multiple pregnancies (abstract).
Kamps (International Journal of Molecules Sciences 18(2): 57 pgs., 2017) teaches cPAL and nanoballs are “established protocols… robust for clinical use” (pg. 30, fourth paragraph) and determining risk in “pre-implantation genetic diagnosis” (abstract).
[Step 2B: No]
Conclusion: Claims are Directed to Non-statutory Subject Matter
For these reasons, the claims, when the limitations are considered individually and as a whole,
are directed to an abstract idea and lack an inventive concept. Hence, the claimed invention does not
constitute significantly more than the abstract idea, so the claims are rejected under 35 USC § 101 as
being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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, 6, and 9-22
Claims 1, 6, and 9-22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shendure (US 20150105267 A1; newly cited) in view of Drmanac (US 20140323316 A1; newly cited), Hyland (US 20130073214 A1; newly cited), and Chudova (US 20160019338 A1; newly cited).
Claim 1 recites obtaining whole genome sequencing data from the embryo, the embryo's male parent, and the embryo's female parent; aligning the embryo sequencing data to a reference genome and identifying variations in the embryo sequencing data relative to the reference genome; aligning the male parent's sequencing data and the female parent's sequencing data to the reference genome and identifying variations present in the parent sequencing data relative to the reference genome; comparing the variations identified in the aligning steps to identify inherited genetic variations in the embryo, wherein the inherited genetic variations are present in the embryo sequencing data and at least one parent's sequencing data; and filtering the variations identified in the first aligning step that were not identified as inherited genetic variations in the filtering step through a variation allele frequency (VAF) threshold, wherein the filtered variations having a VAF above the threshold are identified as de novo genetic variations;
Shendure teaches determining sites in the fetal DNA but not in the maternal or paternal DNA based on comparison to a reference sequence (pg. 12, paragraph [103]) which is based on genomic sequence data (pg. 12, paragraph [101]). Shendure teaches a filtering step to identify de novo mutations (pg. 12, paragraph [103]). Shendure teaches determining minor allele frequency (pg. 2, paragraph [18]), which is a more specific metric of variant allele frequency, but not as a filter for sequence data.
Shendure does not teach variation allele frequency as a filter metric nor application to embryos.
Drmanac teaches determining sequence variation in an embryo by screening prior to implantation (pg. 15, paragraph [183]).
Hyland teaches a “low frequency variant filter” which “can exclude a less common allele (alternate call) when the percentage of reads of the less common allele is below an allele frequency threshold” (pg. 10, paragraph [114]).
Shendure teaches SNPs as possibly pathogenic (pg. 3, paragraph [23]), but does not teach comparison to a database to determine a risk of pathogenic mutations in the embryo.
Chudova teaches comparison of genetic data suggesting a syndrome to ClinVar, which is an archive of relationships among sequence variation and human phenotype (pg. 48, Table 5), where ClinVar teaches a pathogenicity risk. Chudova also teaches application to embryos (pg. 45, paragraph [451]).
Claim 6 recites he VAF threshold in step e) is between 0.25 to 0.45 or 0.3 to 0.4 or is about 0.35. The specification discloses “about” refers to at least +/- 10% of the recited value.
Hyland teaches excluding a less common allele using a variant filter (pg. 10, paragraph [114]). Hyland teaches low frequency variants having a frequency of less than 0.5 (pg. 1, paragraph [7]), which is within 10% of the recited 0.45 threshold.
Claim 9 recites the genetic variations include single nucleotide polymorphisms (SNPs), insertions or deletions (indels), copy number variations (CNVs), and/or structural variations.
Shendure teaches variations including SNPs (pg. 3, paragraph [23]).
Hyland teaches variations including SNPs, indels, and CNVs (pg. 8, paragraph [91]).
Chudova teaches variations include CNVs (abstract).
Claim 10 recites the inherited genetic variations include autosomal dominant, autosomal recessive, compound heterozygous, and/or X-linked genetic variations.
Shendure teaches diagnosis of both recessive and dominant disorders (pg. 8, paragraph [63]).
Claim 11 recites the whole genome sequencing data from the embryo is obtained by culturing the embryo, performing a biopsy on the embryo, amplifying genomic DNA from the biopsy, and sequencing the amplified genomic DNA.
Shendure teaches amplifying and sequencing DNA cell-free DNA (pg. 2, paragraph [20]) but not culturing an embryo or performing a biopsy.
Drmanac teaches culturing cells (pg. 9, paragraph [122]) and biopsy from a blastocyst embryo (pg. 10, paragraph [138]).
Claim 12 recites the biopsy is a trophectoderm biopsy.
Drmanac teaches trophectoderm biopsy (pg. 10, paragraph [138]).
Claim 13 recites the trophectoderm biopsy is performed on day 5 or day 6 of culture.
Drmanac teaches trophectoderm biopsy on a blastocyst (pg. 10, paragraph [138]), where a blastocyst is a 5-6 day old embryo.
Claim 14 recites wherein the genomic DNA is amplified from the biopsy using multi-displacement amplification (MDA).
Drmanac teaches multiple displacement amplification (pg. 9, paragraph [123]).
Claim 15 recites the genomic DNA is sequenced using DNA nanoball sequencing.
Drmanac teaches nanoball sequencing (pg. 5, paragraph [89]).
Claim 16 recites the DNA nanoball sequencing is performed with combinatorial probe anchor
ligation (cPAL).
Drmanac teaches sequencing performing used cPAL (pg. 10, paragraph [135]).
Claim 17 recites the reference genome is a Genome Reference Consortium Human Build.
Shendure teaches alignment to the human reference genome sequence hg19 (pg. 9, paragraph [71]), also known as Genome Reference Consortium human build 37.
Claim 18 recites two or more embryos from the same parents are screened.
Chudova teaches transferring multiple embryos during in vitro fertilization (pg. 44, paragraph [451]).
Claim 19 recites transferring the embryo into the female parent's, or a surrogate's, uterus.
Chudova teaches transferring embryos (pg. 44, paragraph [451]).
Claim 20 recites the embryo is a human embryo.
Shendure teaches application to a human (pg. 8, paragraph [63]).
Claim 21 recites an IVF process comprising fertilizing an egg from a female parent with a sperm from a male parent, culturing the fertilized egg, thereby producing an embryo, screening the embryo for pathogenic genetic variations using the method of claim 1, and transferring the embryo into the female parent's, or a surrogate's, uterus.
Drmanac teaches “pre-implantation genetic diagnosis” (pg. 15, paragraph [182]), where an embryo would require fertilization of egg with a sperm, culturing cells (pg. 9, paragraph [122]) and biopsy from a blastocyst embryo (pg. 10, paragraph [138]) and “embryo screening” (pg. 15, paragraph [183]), and finally transferring reads on implantation, and Drmanac teaches pre-implantation, implying an implantation step which would produce a baby. Chudova also teaches embryo transfer to cause pregnancy following in vitro fertilization (pg. 44, paragraph [451]).
Claim 22 recites the steps of claim 1 except they are applied to a phenotypic trait rather than a pathogenic variation.
Shendure teaches “Mendelian disorders” (pg. 1, col. 1, paragraph [5]) and diseases such as Parkinson’s (pg. 2, col. 1, paragraph [10]), while Chudova teaches at least use of fetal and maternal DNA and their relationship to phenotypes (pg. 12, paragraph [149]). A pathogenic trait is interpreted as a species of the genus phenotypic trait, and thus teachings of disease states read on phenotypic states.
Combining Shendure, Drmanac, Hyland, and Chudova
Shendure teaches determining sites in the fetal DNA but not in the maternal or paternal DNA based on comparison to a reference sequence (pg. 12, paragraph [103]) which is based on genomic sequence data (pg. 12, paragraph [101]). Prior art Drmanac teaches embryo screening as part of genetic diagnosis (pg. 15, paragraph [182-183]). It would have been obvious to one of ordinary skill in the art to replace the screening at the fetal stage as performed by Shendure with screening at the embryonic stage as taught by Drmanac because the screening against a reference steps are similar and thus the results were reasonably predictable.
The claimed invention teaches a filter based on variant allele frequency. Prior art Shendure teaches filters to remove artifacts or problematic sequence information (pg. 5, paragraph [40]). Hyland teaches a method of mapping reads to a reference and scoring variants including filtering less frequent alleles, as determined by a low frequency variant filter (pg. 10, paragraph [114]). It would have been obvious to one of ordinary skill in the art to replace one sequence quality filter with another for the purposes of de novo mutation determination because one of ordinary skill in the art would have been able to carry out such a substitution, and the results were reasonably predictable.
Further combination with Chudova, which teaches using sequence data to determine syndromes, would be obvious because Chudova teaches determining phenotypic information from sequence data and mapping the ClinVar database, because it is a database that describes structure and prevalence of variants (pg. 48, paragraph [488]), including pathogenicity, and thus would be valuable for determining de novo mutation pathogenicity. Shendure and Chudova are both applicable to embryo or fetal screening and their combination would be expected to succeed.
Therefore, the invention is prima facie obvious.
Claims 2-3
Claims 2-3 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shendure in view of Drmanac, Hyland and Chudova as applied to claims 1, 6, and 9-22 above and further in view of Reese (US 20130332081 A1; newly cited).
Claim 2 recites using one or more pathogenicity prediction algorithms to predict if any of
the genetic variations not identified as known pathogenic genetic variations in the comparing step above are pathogenic genetic variations.
Reese teaches “to identify mutated genes and their disease-causing variants in genome-wide searches” (pg. 15, paragraph [159]).
Claim 3 recites the one or more pathogenicity prediction algorithms include SIFT, Polyphen2
HVAR, MutationTaster2, MutationAssessor, FATHMM, or FATHMM MKL.
The previously combined art does not teach use of these algorithms.
Reese teaches SIFT (pg. 15, paragraph [159]).
Combining Shendure, Drmanac, Hyland, Chudova, and Reese
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Reese, which teaches mutation detection using SIFT, which the previously combined works because Reese teaches metrics of deleteriousness in phenotype-causing genetic variants, where such an algorithm is useful for overcoming the bottleneck of variant annotation caused by analysis of genomic data (pg. 1, paragraphs [3-4]). Reese and at least Shendure and Chudova are related to detecting potentially pathogenic variation and their combination would be expected to succeed. Therefore, the invention is prima facie obvious.
Claim 5
Claim 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shendure in view of Drmanac, Hyland and Chudova as applied to claims 1, 6, and 9-22 above and further in view of Samocha (bioRxiv 148353, 32 pgs., 2017; newly cited).
Claim 5 recites predicting a variation to be a pathogenic genetic variation requires that a variation has a MPC score of greater than about 2 and/or a Phred scaled CADD score of greater than about 20. The specification discloses “about” refers to at least +/- 10% of the recited value.
Samocha teaches an MPC score of greater than or equal to 2 (pg. 5, first paragraph).
Combining Shendure, Drmanac, Hyland, Chudova, and Samocha
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Samocha, which teaches deleteriousness prediction, because Samocha teaches a metric for detecting missense variation (abstract), which has been applied to parent-child trios (pg. 2, last paragraph). Samocha and at least Shendure, Drmanac, and Chudova are related to detecting potentially pathogenic variation including in parent-child situations, and their combination would be expected to succeed. Therefore, the invention is prima facie obvious.
Claim 7
Claim 7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shendure in view of Drmanac, Hyland and Chudova as applied to claims 1, 6, and 9-22 above and further in view of Khera (US 20190017119 A1; newly cited).
Claim 7 recites the database of known pathogenic genetic variations is ClinVar, and wherein determining that a genetic variation is a pathogenic genetic variation in step f) requires that the genetic variation has a clinical significance value of pathogenic or likely pathogenic in the ClinVar database.
Chudova teaches use of ClinVar (pg. 48, Table 5) but not a specific metric of pathogenicity.
Khera teaches inclusion of variants if they are deemed clinically significant in ClinVar (paragraph [446]).
Combining Shendure, Drmanac, Hyland, Chudova, and Khera
An invention would have been obvious to one of ordinary skill in the art if some motivation in the prior art would have led that person to modify prior art reference teachings to arrive at the claimed invention prior to the effective filing date of the invention. One would have been motivated to combine the work of Khera, which teaches use of ClinVar for determining whether a mutation is pathogenic (paragraph [446]), which is online and thus widely available to determine mutation specificity. At least Chudova also teaches use of ClinVar to analyze syndromes associated with mutations (pg. 48, Table 5), and thus this combination would be expected to success and be prima facie obvious.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Robert J Kallal whose telephone number is (571)272-6252. The examiner can normally be reached Monday through Friday 8 AM - 4 PM EST.
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/R.J.K./Examiner, Art Unit 1685
/JANNA NICOLE SCHULTZHAUS/Examiner, Art Unit 1685