DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. This action is in response to the papers filed May 22, 2026. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Applicants election of MYO7A, CDH23, and CLRN1 in the reply filed on January 20, 2026 is reiterated for the record.
Claims 1-5, 7-8, 11-13, 15, 17-22 are currently pending.
Claims 2, 12, and 20-22 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected subject matter (a non-elected invention or non-elected species), there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on replies filed on October 31, 2025 and January 20, 2026.
The claims have been examined to the extent that the claims read on the elected combination of genes (CDH23, CLRN1, and MYO7A). The additionally recited genes have been withdrawn from consideration as being directed to non-elected subject matter. Prior to allowance of the claim, any non-elected subject matter that is not rejoined with any allowed elected subject matter will be required to be removed from the claims.
Claim Rejections - 35 USC § 112(b)
3. 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, 7-8, 11, 13, 15, and 17-19 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.
Regarding Claims 1, 3-5, 7-8, it is not clear how the recited preamble is intended to breathe life and meaning into the claim. The preamble of the claim recites a method for testing a patient for a hereditary hearing loss disorder, yet the method only requires “extracting” genomic DNA from a biological sample obtained from a patient; “generating” a library comprising a plurality of bait-captured gene sequences corresponding to a plurality of hereditary hearing loss-related genes, wherein the plurality of hereditary hearing loss-related genes comprises CDH23, CLRN1, MYO7A; and “detecting” at least one mutation in at least one of the plurality of bait-captured gene sequences. Thus it is not clear if applicant intends to cover only a method of “extracting”, “generating” and “detecting” OR if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If it is the later, then it appears that the claims are incomplete, as they fail to provide any active steps that clearly accomplish the goal set forth by the preamble of the claims.
Claim Rejections - 35 USC § 102
4. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 3, 4, 11, 15, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krawitz (Molecular Genetics & Genomic Medicine 2014 2(5) 393-401).
As noted in MPEP 2111.02, “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” In the present situation, the process steps are able to stand alone and the preamble limitation is not accorded patentable weight. Accordingly, the claim language of “A method for testing a patient for a hereditary hearing loss disorder” in claim 1 merely sets forth the purpose of the process, but does not limit the scope of the claims. Further the recitation that “said testing comprises testing for Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome” only modifies the preamble and therefore does not limit the scope of the claims.
Regarding Claim 1 Krawitz teaches a method of screening for mutations in genes associated with Usher syndrome using targeted gene enrichment and deep sequencing. Krawitz teaches that 42 unrelated European patients and two affected sisters with Usher syndrome were included in their study. Krawitz teaches that DNA was extracted from blood. Krawitz teaches that they designed a customized SureSelect oligonucleotide library (Agilent, Santa Clara, CA) for the targeted enrichment of known exons of the Usher genes including CDH23,CLRN1, and MYO7A. After enrichment the exons were sequenced on a HiSeq 2500 (Illumina) sequencer (page 394, col 1). The mutations that were detected are reported in Table 1. Table 1 discloses a single mutation in CDH23 and three mutations in MYO7A. Thus Krawitz teaches a method comprising: a) extracting genomic DNA from a biological sample obtained from a patient, b) generating a library comprising a plurality of bait-captured gene sequences corresponding to a plurality of hereditary hearing loss-related genes (the SureSelect library), wherein the plurality of hereditary hearing loss-related genes comprises CDH23, CLRN1, and MYO7A, and c) detecting at least one mutation in at least one of the plurality of bait-captured gene sequences.
Regarding Claim 3 Krawitz teaches a method wherein the detecting step is performed using high throughput massive parallel sequencing (HiSeq 2500) (page 394).
Regarding Claim 4 Krawitz teaches a method wherein the biological sample is whole blood (page 394).
Regarding Claim 11 Krawitz teaches a method of screening for mutations in genes associated with Usher syndrome using targeted gene enrichment and deep sequencing. Krawitz teaches that 42 unrelated European patients and two affected sisters with Usher syndrome were included in their study. Krawitz teaches that DNA was extracted from blood. Krawitz teaches that they designed a customized SureSelect oligonucleotide library (Agilent, Santa Clara, CA) for the targeted enrichment of known exons of the Usher genes including CDH23,CLRN1, and MYO7A. After enrichment the exons were sequences on a HiSeq 2500 (Illumina) sequencer (page 394, col 1). The mutations that were detected are reported in Table 1. Table 1 discloses a single mutation in CDH23 and three mutations in MYO7A. Thus Krawitz teaches a method comprising: a) extracting genomic DNA from a biological sample obtained from a patient, b) generating a library comprising a plurality of bait-captured gene sequences corresponding to a plurality of hereditary hearing loss-related genes (the SureSelect library), wherein the plurality of hereditary hearing loss-related genes comprises CDH23, CLRN1, and MYO7A, and c) detecting at least one mutation in at least one of the plurality of bait-captured gene sequences. While Krawitz teaches all of the claimed method steps, Krawitz is silent with respect to CDH23, CLRN1, and MYO7A genes being associated with Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome. However this art rejection is set forth because it teaches a broad interpretation of the claims which does not require such a correlation. In the instant case the limitation that the hereditary hearing loss related genes are associated with Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome merely sets forth properties of the genes but does not limit the scope of the claims.
Regarding Claim 15 Krawitz teaches a method wherein the biological sample is whole blood (page 394).
Regarding Claim 17 Krawitz teaches a method wherein the detecting step is performed using high throughput massive parallel sequencing (HiSeq 2500) (page 394).
Response To Arguments- 35 USC 102
5. In the response the Applicants traversed the rejection under 35 USC 102. The Applicants note that claim 1 has been amended to recite the method is a method for "testing a patient for a hereditary hearing loss disorder…wherein said testing comprises testing for Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome". They note that claim 11 has been amended similarly. They argue that Krawitz fails to teach or suggest a panel capable of testing for Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome, as instantly claimed. Krawitz is exclusively directed to Usher syndrome and discloses a gene panel containing only Usher syndrome genes. Krawitz's panel would be incapable of detecting mutations associated with Pendred syndrome, Jervell syndrome, or Lange-Nielsen syndrome.
This argument has been fully considered but is not persuasive. The prior art of Krawitz teaches a method comprising: a) extracting genomic DNA from a biological sample obtained from a patient, b) generating a library comprising a plurality of bait-captured gene sequences corresponding to a plurality of hereditary hearing loss-related genes (the SureSelect library), wherein the plurality of hereditary hearing loss-related genes comprises CDH23, CLRN1, and MYO7A, and c) detecting at least one mutation in at least one of the plurality of bait-captured gene sequences. Thus Krawitz teaches each of the active process steps recited in the methods. Regarding Claim 1, the claim language of “A method for testing a patient for a hereditary hearing loss disorder… wherein said testing comprises testing for Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome” merely sets forth the purpose of the process, but does not limit the scope of the claims. Regarding Claim 11, Krawitz is silent with respect to CDH23, CLRN1, and MYO7A genes being associated with Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome. However the art rejection is set forth because it teaches a broad interpretation of the claims which does not require such a correlation. In the instant case the limitation that the hereditary hearing loss related genes are associated with Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome merely sets forth properties of the genes but does not limit the scope of the claims. The rejections are maintained.
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 5 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Krawitz (Molecular Genetics & Genomic Medicine 2014 2(5) 393-401) in view of Kimberling (Genetics in Medicine Nol 12 No 8 August 2010).
The teachings of Krawitz are presented above.
Krawitz does not teach a method wherein the biological sample is from a from an infant patient, the infant patient having or suspected of having a hereditary hearing loss disorder (clm 5, 13).
However Kimberling teaches that in the context of most newborn hearing screening programs, the appropriate time for DNA screening is at the time of follow-up verification of the HL, which occurs between 3 and 12 months of age (page 515). Kimberling discloses a proposed paradigm for screening D/HOH children for Usher syndrome (see Fig 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Krawitz by obtaining a biological sample from an infant suspected of having a hereditary hearing loss disorder as suggested by Kimberling. One of skill in the art would have been motivated to screen infants suspected of having Usher syndrome because Kimberling teaches that for Usher syndrome, early diagnosis has many immediate and several long-term advantages to patients and their families including the election of cochlear implantation and the potential for future treatments to delay the progression of RP (page 515).
8. Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Krawitz (Molecular Genetics & Genomic Medicine 2014 2(5) 393-401) in view of Hess (Biotechnology Advances 41 (2020) 107537).
The teachings of Krawitz are presented above.
Krawitz does not teach a method wherein an adaptor sequence is ligated to at least one end of the plurality of bait-captured gene sequences (clm 7). Krawitz does not teach a method wherein an adaptor sequence is ligated to both ends of the plurality of bait-captured gene sequences (clm 8).
However Hess teaches that NGS can be roughly divided into the process elements of sample preprocessing, library preparation, sequencing itself and bioinformatics (Fig. 1). Regardless of the underlying principles of the respective sequencing method, all modern sequencing technologies require dedicated sample preparation to yield the sequencing library loaded onto the instrument (Goodwin et al., 2016; Metzker, 2010). Sequencing libraries consist of DNA fragments of a defined length distribution with oligomer adapters at the 5′ and 3′ end for barcoding, as well as the actual sequencing process. After sequencing, the generated data is analyzed using bioinformatics (page 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Krawitz by putting adapters on both ends of the bait captured sequences as suggested by Hess. In the instant case Hess teaches that the use of adapters is standard in NGS. One of skill in the art would have been motivated to add adapters at both ends of the captured sequences to render the sequences compatible with the applied sequencing technique.
9. Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Krawitz (Molecular Genetics & Genomic Medicine 2014 2(5) 393-401) in view of Lipson (US 11,118,213 Issued 9/14/2021)
The teachings of Krawitz are presented above.
Krawitz does not teach a method further comprising the use of at least 5,000 nucleic acid probes.
However Lipson teaches a method of using bait sequences to capture targets for nucleic acid sequencing. Lipson teaches that the bait set is greater than 5000 probes (Col 58, lines 28-32).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Krawitz by using at least 5000 nucleic acid bait probes as suggested by Lipson. In the instant case Lipson teaches that any number of bait probes can be used. It would have been obvious to use 5000 probes for the benefit of being able to capture a larger number of target genes for sequencing.
10. Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Krawitz (Molecular Genetics & Genomic Medicine 2014 2(5) 393-401) in view of Lipson (US 11,118,213 Issued 9/14/2021) and Rosenthal (US 2022/0275457 Filed 1/18/2022).
The teachings of Krawitz and Lipson are presented above.
The combined references do not teach a method wherein at least one of the 5,000 nucleic acid probes comprises a region of complementarity to at least one of the plurality of hereditary hearing loss-related genes, the region of complementarity comprising a coding region and 10 bases of an untranslated region (UTR) of the at least one of the plurality of hereditary hearing loss-related genes.
However Rosenthal teaches NGS using baits to capture desired targets for sequencing. Rosenthal teaches that the baits were designed to capture all coding exons and exons/intron boundaries of hereditary cancer genes (para 0082).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Krawitz and Rosenthal by using nucleic acid bait probes that are complementary to a coding region and 10 bases of an untranslated region (UTR) of the at least one of the plurality of hereditary hearing loss-related genes as suggested by Rosenthal. It would have been obvious to use bait probes complementary to the exon/intron boundaries for the benefit of being able to detect mutations at splice sites which can cause exon skipping or intron retention leading to nonfunctional proteins and to ensure higher quality coverage of the coding sequences.
Response To Arguments- 35 USC 103
11. In the response the Applicants traversed the rejection under 35 USC 103. They Applicants argue that the additionally cited prior art references of Kimberling, Hess, Lipson, and Rosenthal are incapable of remedying the deficiencies of Krawitz because none of the cited references, alone or in combination, teach or suggest a panel that includes genes associated with all four hereditary hearing loss syndromes (Usher, Pendred, Jervell, and Lange-Nielsen).
This argument has been fully considered but is not persuasive. The Applicants arguments regarding what is missing in Krawitz have been fully addressed above. The response to Applicants arguments, as set forth above, applies equally to the additional grounds of rejection.
Improper Markush Grouping Rejection
12. Claims 1, 3-5, 7-8, 11, 13, 15, and 17-19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The claims recite the following Markush group:
wherein the plurality of hereditary hearing loss-related genes comprises three or more of ABHD12, ADGRV1, ARSG, CDH23, CEP250, CEP78, CIB2, CLRN1, ESPN, FOX11, GJB2, GJB6, HARS2, KCNE1, KCNJ10, KCNQ1, MYO7A, PCDH15, PDZD7, SLC26A4, USH1C, USH1G, USH2A, and WHRN (claims 1, 9, and 11)
The Markush grouping is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
MPEP 2117(II) states that “A Markush claim may be rejected under judicially approved “improper Markush grouping” principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an “improper Markush grouping” if either: (1) the members of the Markush group do not share a “single structural similarity” or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)).
MPEP 2117(II) further state that alternatives (1) share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class and (2) share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent in the context of the claimed invention.
MPEP § 2117(II)(A) states that “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved”. Herein the members of the Markush grouping are all genes. These do not belong to the same recognized physical or chemical class or to the same art-recognized class because there is no expectation from the art that each of the recited genes would function in the same way in the claimed method. It is only in the context of this specification that it was disclosed that all members of this group may behave in the same way in the context of the claimed invention.
MPEP § 2117(II)(B) states that “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection IIA above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structure feature that is essential to a common use. Again the members of the Markush grouping are all genes. While they are all made up of nucleic acids or amino acids, the structure of comprising nucleic acids or amino acids is not essential to any asserted common use.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response To Arguments- Improper Markush Group
13. In the response the Applicants traversed the improper Markush Group rejection. First the Applicants argue that the claims do not recite a Markush group. They state that claim language defined by a Markush grouping requires selection from a closed group “consisting of” the alternative members. By contrast, the instant claims recite that “the plurality of hereditary hearing loss-related genes comprises three or more of [list of genes]”. Since this is open language it cannot be considered a Markush group.
This argument has been fully considered but is not persuasive. MPEP 2117 states that any claim that recites alternatively usable members, regardless of format, should be treated as a Markush claim.
The Applicants further argue that the all 24 genes in the group share a common property: they are all “hereditary hearing loss-related genes”. As disclosed in paragraph [0077] of the specification, the panel is designed to detect causative genetic alterations involved in all three types of Usher syndrome, in addition to other hearing loss-related disorders, including Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome. The genes thus share a common property of association with hereditary hearing loss. This shared property is responsible for their function in the claimed invention, which is detecting mutations in hereditary hearing loss-related genes. The Examiner's argument appears to be that because the genes are related to different hearing loss disorders, they would not function the same way if used interchangeably in the claimed method. This ignores the very purpose of the invention, which is a single panel of hearing- loss related genes capable of testing for Usher syndrome, Pendred syndrome, Jervell syndrome, and Lange-Nielsen syndrome. By the nature of the invention, the genes must relate to different hearing-loss disorders.
This argument has been fully considered. The examiner agrees that the genes share a common use because they are all disclosed in the specification as being correlated with hereditary hearing loss. However it is not sufficient that the members of a Markush group share only a common use. They must also share a “single structural similarity”. The rejection is maintained.
14. 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Wu-Cheng Shen can be reached at 571-272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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