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 .
Election/Restrictions
Applicant's election with traverse of group I, claims 1, 3-9, 13, 15, and 17 and the combination of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 in the reply filed on 01/25/2026 is acknowledged. The traversal is on the grounds that the same or corresponding technical feature shared by the inventions is the use of the at least one of the 13 SNPs present in the MUC4 gene. The response asserts that the Grocock prior art reference does not teach the above 13 SNPs and discloses in general risk of gastric cancer. The response further asserts Grocock does not disclose MUC4 as a standalone biomarker. This is not found persuasive because the claims are not limited to a common SNP or only MUC4 as a biomarker. The common technical feature between the groups is the MUC4 gene. The recitation of a mutation in at least one loci, does not require all 13 SNPs and thus the common shared feature among the groups is MUC4. Because MUC4 gene is known in the art this is not a special technical feature over Grocock.
The requirement is still deemed proper and is therefore made FINAL.
It is noted that applicant was required to elect a SNP and corresponding NM position, because applicant elected the entire combination of SNPs, the entire combination of mutations is under examination. The claims are being examiner to requiring all of the SNPs and all of the corresponding mutations in dependent claim 6 and 16.
Claims 10-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/25/2026.
Claims 1, 3-9, 13, 15-17 are under examination with respect to the combination of rs774527434, rs534579 185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. Claims 6 and 16 are under examination with regard to the combination of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C.
Claim Rejections - 35 USC § 112
Claims 1, 6, 13 and 16 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 Markush grouping of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 and the grouping of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C 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:
A Markush claim contains an ‘‘improper Markush grouping' ' if: (1) the species of the Markush group do not share a ‘‘single structural similarity,' ' or (2) the species do not share a common use. Members of a Markush group share a ‘‘single structural similarity' ' when they belong to the same recognized physical or chemical class or to the same art-recognized class. Markush group applies when there is an expectation from the knowledge in the art that the members of the class will behave in the same way in the context of the claimed invention. There is no evidence that the members of the claimed classes encompasses a wide range of mutations will behave in the same way in the context of the claimed invention. There is no common use that flows from the substantial structural feature, see MPEP 2117 (II) B. There is no structural feature that is common use for gastric cancer.
The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons: each member of the set of mutations of the claimed loci are structurally unique relative to one another. There is no disclosed common substantial structural feature. The only structural similarity present is that all detected positions are part of nucleic acid molecules. The fact that the markers comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising a nucleotide alone is not essential to the common activity of being correlated with gastric cancer. Accordingly, while the different markers are asserted to have the property of being indicative of gastric cancer, they do not share a single structural similarity. Additionally there is no expectation from the knowledge in the art that the members of the class will behave in the same way in the context of the gastric cancer, in other words there is no expectation from the art that each of the claimed mutations will be associated with predisposition to gastric cancer.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
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.
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, 3-9, 13, 15-17 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 1 recites a method for predicting or diagnosing gastric cancer in a subject comprising detecting a mutation of a muc4 gene wherein the mutation is present at the elected loci rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. Claim 13 recites a method for providing information for predicting or diagnosing gastric cancer comprising detecting a mutation at the elected loci rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. The claim is indefinite because it is unclear how a mutation will be present at all of the elected mutation. It is unclear if the claim is requiring the same mutation is present at each loci, if the claim is requiring that all of the loci comprise a mutation based on the elected combination, or if the claim is requiring more than one mutation at refSNP position. Additionally there is no nexus between the preamble and the process steps. It is unclear if the claim is a method of detecting a mutation or as recited in the preamble a method of predicting or diagnosing cancer. None of the active process steps predict, diagnose or provide information. It is unclear if one necessarily accomplishes what is intended for the method by practicing the recited methods steps. The claims are indefinite because limitation in the preamble is not recited in the process and the recitation of a mutation is vague and indefinite resulting in the metes and bounds of the claim being vague and indefinite and it is unclear if one necessary accomplishes what is intended for the method by practicing the recited method steps.
Claim 6 and 16 are indefinite over the recitation of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C. This recitation renders the claim indefinite. Claim 6 and 16 depend from claim 1 and claim 1 recites mutations at 13 elected loci however claim 6 and 16 recite only 11 mutations. Additionally the recitation of claim 6 and 16 do not further limit refSNP positions. The recitation and nomenclature in claims 6 and 16 is not equivalent to the refSNP positions recited in claim 1. Additionally commensurate in scope with the claimed elected refSNP and corresponding NM positions it is unclear if the claim is requiring that all of the mutations are present at each of the locations.
With regard to claim 6 and 16, the recitation of mutations selected from the group consisting of “NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C” is considered essential subject matter. Therefore the claims are rejected as being incomplete for omitting essential elements, such omission amount to a gap between the elements. See MPEP 2172.01. The omitted elements are the mutations at NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C. As provided in 2144.01(III) “The goal of the Office is to build a comprehensive database that can be used for, inter alia, assessing the prior art. It is therefore essential that all sequences, whether only disclosed or also claimed, be included in the database. In those instances in which prior art sequences are only referred to in a given application by name and a publication or accession reference, they need not be included as part of the “Sequence Listing”, unless the referred-to sequence is “essential material” per MPEP § 608.01(p).” Here, the mutation “NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>” is essential as it is required element of the claims. It is further noted 37 CFR 1.57(h)(1) “authorizes the correction of noncompliant incorporation by reference statements that do not use the root of the words "incorporate" and "reference" in the incorporation by reference statement when the application as filed clearly conveys an intent to incorporate the material by reference. This correction can usually be made, for example, when an originally filed claim of an application identifies an amino acid or nucleotide sequence by database accession number. In making the determination of clear intent the examiner should consider the language used in referencing the sequence, the context in which it is disclosed, and any additional arguments or evidence presented by applicants.”
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 6 and 16 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 6 and 16 recite where the mutation is one or more mutations selected from the group consisting of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C. This claim does not further limit claim 1. Claim 1 requires a mutation is present at one or more loci from the group consisting of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. The loci represented by rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 comprise one allele and the loci comprise 13 positions for a single nucleotide position. The mutations of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C comprise 11 positions and do not further limit the 13 SNP locations or the mutation as claimed in claim 1. The mutations recited in claim 6 and 16 are not further limiting the refSNP or mutation of claim 1. Additionally there are less mutations recited in claim 6 and claim 16 as there are in claim 1 and it is not clear how claim 6 and 16 is to further limit claim 1. 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 § 112- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-9, 13, 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims encompass methods of detecting a mutation at the elected loci combination rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 and mutations comprising the elected mutations NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C for predicting or diagnosing gastric cancer. The claims encompass detecting mutations at each of the elected loci and include detecting each of the claimed mutations NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C. Commensurate in scope with the elected invention, the claims encompass detecting mutations at each of the elected loci positions and include specific mutations NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C. Addition claims require the mutation suppresses expression of MUC4 gene in noncancerous gastric mucosa and mutation increased expression of MUC4 gene in gastric cancer compared to normal gastric tissue.
The claims require that a mutation is present at each of the elected loci and dependent claims require that mutations are NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C, requiring all of the mutations present. Additional claims require knowing mutations result in suppressing expression of MUC4 in noncancerous gastric mucosa and which mutations result in increasing expression of MUC4 gene in gastric cancer. Additional claims further require the mutation in subjects with stomach adenocarcinoma, colorectal cancer, and endometrial cancer (claim 9).
When the claims are analyzed in light of the specification, the claims encompass methods which require analysis of the elected combination of loci and elected combination of mutations in any subject, human and non-human subjects, where the specification is silent to whether these mutations exist in any other species. Additionally the specification is silent to any human subject comprising ALL of the mutations or comprising a mutation at ALL of the loci, which is encompassed by the claims and elected combination. The claims further encompass any mutation and include any structurally undefined SNP that is present or absence at any of the positions of the refSNP citations is associated with gastric cancer, increased expression of MUC4 in gastric cancer or suppresses expression in noncancerous gastric mucosa.
The genus of mutations encompassed by the claims is a broad variable genus. While the claims recite loci rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645, this only indicates the position of the mutation and does not define the structural requirements of the mutation. The genus encompassed by the claims is a broad variable genus and encompasses any genetic alteration at the claimed loci. Neither the claims or the specification describe a subject that is predisposed or has gastric cancer that has mutations at each of the elected loci. The specification teaches allelic changes and frequency of 10 of the 13 claimed loci (see table 2). However the claims are not limited to the recited allelic changes in table 2. Table 2 further describes the allele frequences and demonstrates that not all of the even 10 alleles will be present in one subject.
The specification describes the frequence of three SNPs in stomach adenocarcinoma, colorectal cancer, and endometrial cancer (ex 3, table 6). While the specification describes the frequency of rs774527434, rs534779185, and rs77250903, the specification does not describe the mutation present at the refSNP position.
The specification describes MUC4 expression in gastric tissue in subjects with MUC4 mutation rs774527434 (ex 4). The specification does not describe which mutation is present at rs774527434 that corresponds to MUC4 expression. The specification does not describe any other mutation that corresponds to MUC4 expression.
Because the claims encompass a broad, variable genus of any type of mutation at the combination elected loci of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. The alleles set forth in the specification are not representative of the broad variable genus encompassed by the claims because the specification provides no structure/function correlation or any other relevant identifying characteristic between the mutations in MUC4 and gastric cancer. The skilled artisan would not be able to distinguish between members of the claimed genus versus non-members.
Relevant to the lack of particular structural limitations in the rejected claims drawn to nucleic acids, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
In analysis of the claims for compliance with the written description requirement of 35 U.S.C. 112, first paragraph, the written description guidelines note regarding genus/species situations that “Satisfactory disclosure of a ``representative number'' depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed.” In the instant case, the specification fails to teach the necessary common attributes or features of the genus of encompassed nucleic acids and cancers in view of the species disclosed. The skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides and/or proteins, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid itself is required. As such, one of skill in the art would not recognize that applicant was in possession of the genus of mutations encompassed by the broadly claimed invention. Thus considering the breadth of the breadth of the claimed nucleic acids, cancers and their specific required functionalities, in light of the teachings of the instant specification and the art, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter
Claim Rejections - 35 USC § 112- Enablement
Claims 1, 3-9, 13, 15-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Nature of the invention and breadth of the claims
The claimed methods are drawn to predicting or diagnosing gastric cancer in a subject by detecting a mutation of a mucin 4 gene present at the elected loci of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645. Additional claims require mutation is the elected combination of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C.
Dependent claims encompass mutation that suppresses expression of MUC4 in noncancerous gastric mucous and increased expression in gastric cancer tissue. Additional claims require the subject has stomach adenocarcinoma, colorectal cancer, endometrial cancer and the gastric cancer is diffuse-type gastric cancer, intestinal type gastric cancer, and mixed-type gastric cancer.
The claims generically encompass any mutation at the combined positions of rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 is associated with diagnosing or predicting gastric cancer, including diffuse-type gastric cancer, intestinal tyupe gastric cancer, and mixed-type gastric cancer.
Additional claims encompass the combination of NM_018406.7:c.5375C>T, NM_018406.7:c.5005T>C, NM_018406.7:c.7658G>A, NM_018406.7:c.11180G>C,NM_018406.7:c.15884G>A, NM_018406.7:c.10673G>A, NM_018406.7:c.6064G>A, NM_018406.7:c.7648G>T, NM_018406.7:c.6638C>T, NM_018406.7:c.6640G>T, and NM_018406.7:c.3053G>C is associated with diagnosing or predicting gastric cancer.
The claims thus require knowledge of reliable and robust association between the mutations at rs774527434, rs534579185, rs77250903, rs868067409, rs531395109, rs754808151, rs1304612772, rs774907241, rs771925912, rs745342765, rs148735556, rs11717039, and rs547775645 with gastric cancer.
Direction provided by the specification and working example
The instant specification provides example wherein samples from 19 human subjects with gastric cancer from 14 families in which 2 or more gastric cancer cases were evaluated by whole exome sequencing (ex 1). The specification asserts that 14 MUC4 mutations were found and 10 mutations were selected with LOD values greater than 0 (see ex 2, table 2). The specification teaches that 5 subjects had two different mutations (see para 75 and table 2). The specification does not teach any subject having 10 or 13 mutations, as consistent with the elected combination. The specification does not teach which two mutations are found in patients with gastric cancer.
The specification teaches analysis of the association of MUC4 mutation and gastric cancer in a larger cohort. The specification teaches that two mutations, rs148735556 and rs11717039 were detected in MUC4 lesions (see table 4 and para 85). The specification does not teach which allele is the causative allele for gastric cancer. The data in the specification only describes A1 and A2 but does not demonstrate which of the alleles is associated with gastric cancer. The specification further asserts that rs547775645 missense mutation was identified as significant (see table 5).
The specification asserts that the quality of the 10 rare mutations (associated with eh elected combination) was poor and could not be tested. The response asserts that a common mutation existed in MUC4 that had a significant association with gastric cancer. The specification does not teach which mutation had a significant association with gastric cancer.
The specification further asserts that the 10 mutations in the MUC4 gene were cancer related and confirmed in gastric cancer, stomach adenocarcinoma, colorectal cancer, and endometrial cancer (see ex 3), however the specification does not teach which allele is associated with each of the cancers and the frequency of the SNPs is less than 5% (see table 6). For example in one patient out of 295, one patient with STAD had a heterozygous rs77452743 SNP but patients with CRC and UCEC did not have the mutation, one patient out of 295 is not statistically significant to diagnose gastric cancer.
The specification further addresses the expression of MUC4 in gastric tissue from subjects with MUC4 mutations (see ex 4). The specification evaluates rs77452743, however the specification does not describe which mutation at rs77452743 was evaluated. The specification asserts that MUC4 mutation shower lower MUC4 positive staining than noncancerous mucous that was wild type, however the specification does not disclose which MUC4 mutation was evaluated or is predictably associated lower MUC4 expression in noncancerous mucous. While the specification asserts 5375G>A was most pronounced, the specification does not provide or evaluate any other mutations or provide evidence that any of the claimed 13 mutations are associated with expression levels of MUC4.
The specification provides verification of association between MUC4 mutation and gastric cancer (see ex 6). The specification evaluates genotyping of rs774527434 and rs531395109. The specification provides that a total of 14 subjects had mutations of which 5 were non-gastric cancer and 9 were gastric cancer patients. The specification evaluated MUC4 mutations with MUC4 expression levels. The analysis provided a p value of .187 demonstrating that the expression levels with MUC4 mutations was not predictably correlated. Additionally the presence of 5 non-gastric cancer and 9 gastric cancer patients out of 14 subject is not predictably correlated to reasonably determine that the presence of any MUC4 mutation is associated with gastric cancer.
It is inconclusive based on the guidance in the specification if any mutation at the claimed elected refSNPs is associated with gastric cancer, including in patients with a family history of gastric cancer or subjects having STAD, CRC, or UEC. The specification provides no guidance on which alleles are predictably associated with the presence of gastric cancer and does not provide analysis of any subject having all the claimed mutations.
Relevant to the breadth of the claims, there is no analysis of any non-human subjects. There is no analysis of which mutations or alleles are associated with gastric cancer. There is no analysis of which mutations or alleles are associated with specific subsets of gastric cancer.
State of the art, level of skill in the art, and level of unpredictability
While the state of the art and level of skill in the art with regard to detecting SNPs in human samples is high, the unpredictability in associating any particular expression with a specific phenotype, diagnosing or predicting gastric cancer, as is encompassed by the claims, is even higher. The unpredictability is demonstrated by the related art and the instant specification.
Because the claims encompass and any subject organism, while the specification teaches only the analysis of human subjects, it is relevant to point out the unpredictability in extrapolating the mutation, or its association with any phenotype, from one animal to any other different animal.
Applicant’s own reference, Choi et al. (PLoS ONE 15(7): e0236197, cited on IDS) demonstrates the unpredictability of associating MUC4 mutations with gastric cancer. Choi teaches 5 gastric cancer patients without MUC4 variants were identified among 4 families with gastric cancer (see pg. 13). Choi teaches the limitations of their study includes a small sample size, could not adjust for confounders. Choi further demonstrates that expression of MUC4 in cancer mucosa was not associated with presence of a MUC4 variant (see fig 3)
It is unpredictably to determine whether any mutation at the claimed loci combination are associated with gastric cancer such that the presence of any allele at the claimed loci would be predictably associated with predicting or diagnosing gastric cancer. Relevant to the elected species, the specification provides no analysis of any subject comprising mutations at the elected combination of positions much less the claimed positions. Additionally it is unpredictable to determine which mutation is associated with a subset of gastric cancers. The specification provides no guidance on the presence of mutations and specific subsets of gastric cancer.
Quantity of experimentation required
A large and prohibitive amount of experimentation would be required to make and use the claimed invention. Given that the claims generically encompass any mutation at the combined elected refSNP positions, one would have to perform large case: control studies, and validation of any results, to determine which mutations may be reliably and robustly associated with diagnosing and predicting gastric cancer. Additionally the claims encompass mutations causing expression changes in MUC4 in gastric mucous. One would have to perform large case: control studies and validation of a large genus of the claimed mutations at the refSNPs positions to determine which mutations are associated with MUC4 expression. Even for the particular mutations disclosed in the specification, given the lack of statistically significant results with regard to the association of gastric cancer, MUC4 expression and mutations, one would have to perform an analysis to see if any mutation are robustly and reliably associated with MUC4 expression or gastric cancer.
Conclusion
Taking into consideration the factors outlined above, including the nature of the invention and breadth of the claims, the state of the art, the level of skill in the art and its high level of unpredictability, and the particular guidance in the specification including the examples, it is the conclusion that an undue amount of experimentation would be required to make and use the invention as claimed.
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, 3-9, 13, 15-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract idea and natural law without significantly more.
Claim 1 recite “detecting a mutation of a mucin 4 gene” and this step encompasses a mental process (i.e. the process of reviewing the data and drawing inferences about mutation) which could be practiced in the mind. Claim 13 recites a method for providing information for predicting or diagnosing gastric cancer and this recitation encompasses an abstract idea of mental process of evaluating information to reach a conclusion. Claim 17 additionally sets forth the method determines the gastric cancer when the mutation of the MUC4 gene is detected after the detecting the mutation of the MUC4 gene and this sets forth both another mental process as well as the correlation between mutation in MUC4 gene and gastric cancer which is a law of nature.
Claims 1 and claim 13 set forth a law of nature, which is a natural correlation between the presence of mutation in MUC4 gene at the claimed elected loci and gastric cancer. The recited relationship is a natural phenomenon that exists apart from any human action. This type of correlation is a consequence of a natural process.
These judicial exception are not integrated into a practical application because the steps in addition to the judicial exceptions are data gathering steps that do not apply or integrate the judicial exceptions in any way. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the steps in addition to the judicial exception are data gathering steps recited at a high level of generality employing techniques that were well-established, routine and conventional at the time of the invention. The courts have recognized that amplifying and sequencing nucleic acid sequences is among the well-understood, routine, conventional activity in the life science arts when claimed in a merely generic matter. Here, the claims include steps of extracting genomic DNA from a sample of a subject and detecting a mutation at the elected loci l with dependent claims requiring amplifying (claim 15) or detecting by detection agents comprising primers, probes (claim 7). Prior to the invention, Esser (BMC Genomics, 2017, 18:517, pp 1-15) teaches whole genome and exome sequencing data of individuals gastric cancer sample. Esser teaches that sequencing gastric cancer samples was routine and known in the art. Furthermore, Moon (Scientific Reports, 2019, 9:1382, pp 1-11) teaches genome wide association studies using a SNP array that is a KoreanChip Axiom array (see array context, pg. 2, table 2). The specification discloses using a KoreanChip and Moon discloses the Korean chip was commercially available, demonstrating it was routine, conventional and well-known in the art to evaluate SNPs, including SNPs in MUC4 by hybridization assays. The prior art demonstrates the methods used by the instant specification to identify mutations in the MUC4 gene was routine, conventional and well known in the art.
Claims 3, 4 recite additional natural phenomenon, the claims recites wherein the mutation increased expression and mutation suppresses expression. These recitations are a natural phenomenon that exists apart from any human action. This type of correlation is a natural law.
Claims 5 and 6 recite specific mutations, claim 8 recites specific gastric cancer and claim 9 limits the subject. These limitations are a field of use limitation which does not amount to significantly more.
Claims 7 and 15 limit the detection steps, which is addressed by Esser and Moon.
Claim Rejections - 35 USC § 102
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, 3-5, 7-8, 13, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Moon (Scientific Reports, 2019: 9: 1382, pp 1-11).
Moon teaches genotyping samples using KoreanChip, Affymetrix 5.0 and Illumina exome array. Moon teaches whole genome association studies (see GWAS, table 3). Because the claim recites detecting a mutation at the combined elected loci and the claims do not require what mutation is being detected, Moon anticipates the claimed invention. The claim does not require any other active steps other than detecting a mutation. There is no active process steps that require diagnosis or predicting gastric cancer. With regard to a subject having family history of gastric cancer, in the population of Moon there will inherently comprise a sample that includes a subject with a family history of gastric cancer. The claim does not require a specific primer or probe or require any specific allele to be detected, as such the assay of Moon which encompasses whole genome analysis will inherently detection a mutation, including either allele at the claimed loci positions. Furthermore the specification teaches KoreanChip for analysis of MUC4 mutations, as such the KoreanChip of Moon will detect MUC4 mutations.
Claims 1, 3-5, 7-8, 13, and 17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Esser (BMC genomics 2017, 18:517:1-15).
Esser teaches whole genome and exome sequencing data of individual gastric cancer samples. Esser teaches analysis of two different sequencing platforms to evaluate two patients for deep sequencing analysis (see study patients). Because Esser teaches a subject with gastric cancer, the subject will necessarily be a subject with family history of gastric cancer. Additionally the specification teaches whole exome sequencing for analysis of mutations at the claimed elected loci. Because both Esser and the instant specification teach the same analysis, Esser necessarily will detect the positions claimed. The claim does not require a specific allele at each of the positions as such any sequencing of the claimed loci will detect a mutation, which is taught by Esser. The claim does not require a specific primer or probe or require any specific allele to be detected, as such the assay of Esser which encompasses whole exome sequencing will inherently detection a mutation, including either allele at the claimed loci positions.
Conclusion
No claims are allowable.
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/SARAE L BAUSCH/ Primary Examiner, Art Unit 1699
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