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 .
Application Status and Election
Claims 2-5, 7-8, 21-23, 29-33, 45-48, 50 and 52 are pending.
Applicant’s election without traverse of group I, directed to methods of treating cancer by inhibiting expression of a variant nORF, encompassing claims 2-5, 7-8, 45-48, 50 and 52 in the reply filed July 6, 2026 is acknowledged. Claims 21-23 and 29-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected groups, there being no allowable generic or linking claim.
Applicant’s election of the small molecule inhibitor (top) in claim 52 and ENST00000427352.1 as the variant nORF is acknowledged. Treating cancer with the elected small molecule that acts to inhibit expression of a variant nORF is free of the art. The species election was broadened to include an siRNA inhibitor. Claims 5 and 7-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim.
Claims 2-4, 45-48, 50 and 52 are under examination.
Information Disclosure Statement
The U.S. Applications cited on the information disclosure statement filed 9/22/23 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the US Applications listed under US Patent Documents are not considered U.S. patent documents (published). The examiner suggests citing the pre-grant U.S. publications that correspond to these applications. The IDS has been placed in the application file, but the information referred to in the US Applications has not been considered as to the merits. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Drawings
The drawings are objected to because the lines, shadings, numbers and letters of FIGs 1-2 are not sufficient to provide satisfactory reproduction characteristics. 37 CFR 1.84(l) states that “all drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined.” In the instant case, the text in FIGs 1-2 is light grey or otherwise not sufficiently dense and dark, or is very small and of poor resolution to permit satisfactory reproduction characteristics.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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.
Claim 50 is 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 50 recites “wherein the nORF has at least 80% identity to SEQ ID NO 1 or 2.” SEQ ID NOs 1 and 2 are amino acid sequences, whereas an nORF is known in the art and described in the specification as an open reading frame, which is a DNA sequence that codes for a protein. It is confusing how a nucleic acid sequence can be composed of amino acids.
To overcome this rejection, it is suggested that claim 50 recite “where in the nORF encodes a protein having at least 80% identity to SEQ ID NO: 1 or 2.”
Claim Interpretation
Claim 1 recites “a variant nORF”, “an nORF” and a “cORF”. The Specification indicates that an “nORF” is an acronym for “novel ORF”, which is distinct from a canonical open reading frame “cORF” (page 6). The Specification then indicates that a “variant nORF” is a genetic variant of an nORF, without explaining how the ORF varies, such as in expression level, or amino acid sequence, etc. (page 6). However, claim 1 also recites that “the nORF is present in… (vi) a region not associated with the cORF or the gene”. Thus, it appears that there does not need to be any relationship between the nORF and its “distinct cORF”. Furthermore, if an nORF is indeed “novel” then the variant of the “nORF” would likewise be novel. As such, any nORF that has at least one known SNP, which is virtually every ORF, could then also be interpreted as a variant nORF. Because there does not appear to be any relationship between an nORF and a cORF other than they are distinct from each other, an “nORF” and is interpreted as any open reading frame, and a “variant nORF” is interpreted as any open reading frame that differs from a version, either in nucleotide sequence or expression, of the respective nORF.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 2-4, 45-48, 50 and 52 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.
MPEP 2163.II.A3.(a).(i) states, “whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
For claims drawn to a genus, MPEP 2163.II.A3.(a).(ii) states, “written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species” where “representative number of species' means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 2 recites “an inhibitor that reduces expression of a variant nORF”, which represents a genus of molecules that are defined by their function of inhibiting expression of an ORF, rather than their structure. Additionally, as indicated above the claimed “variant nORF” can be virtually any open reading frame. Some such inhibitors are described in the specification on pages 8-10, including small molecules, polynucleotides or polypeptides. Because there is a known correlation between the structure of RNAi-based inhibitors and their function to reduce expression of a known target mRNA or gene sequence, one skilled in the art could have predicted the structure of RNAi-based inhibitors that have the claimed inhibitor function of a given known nORF. However, for the reasons described below, Applicants have not sufficiently described the genus of small molecules or antibodies that have the claimed function of reducing expression of a variant nORF such that one skilled in the art could have reasonably concluded applicants had possession of the genus as claimed. Additionally, Applicants have not sufficiently described the genus of variant nORFs that are associated with cancer.
The claims recite a polypeptide, including an antibody or antigen-binding fragment, and a small molecule and therefore only identify the polypeptide, antibody and/or small molecule by function. No structure is recited that correlates to the claimed function of inhibiting expression of the nORF. A definition by function does not suffice to define the genus because it is only an indication of what the antibody or small molecule does, rather than what it is. To provide adequate written description and evidence of possession of the claimed polypeptide or small molecule that can inhibit expression of nORF, the instant specification in view of the art must structurally describe representative polypeptides and small molecules that function as an inhibitor or expression, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
The specification is completely silent on the structure of antibodies and small molecules that are capable of inhibiting gene expression. Additionally, the prior art has yet to discover antibodies and/or small molecules are capable of reducing expression of a specific gene, rather than a global reduction of gene expression. Although the Specifically discloses the structures of three small molecules that could potentially bind to the singly described variant nORF’s translation product (page 23), Applicants do not demonstrate or suggest wether the compounds could affect the expression of the variant ENST00000427352.1. Applicant failed to treat cells with the compounds and then measure transcript or protein levels of the variant ORF or the translation product of ENST00000427352.1. There is no evidence that the compounds could promote degradation of the variant nORF translation product.
As indicated above, a BRI of “a variant nORF” is nearly every ORF, since the Specification fails to provide any limiting definition or description. However, even if “variant nORF” were interpreted narrowly as an ORF that codes for a microprotein/micropeptide and is found in an intron, 5’ UTR, 3’UTR or expression from a lncRNA, and codes for a peptide variant only found in cancer vs noncancerous cells, the genus of expression inhibitors would also be insufficiently described, since the genus of “variant nORFs” having the limited interpretation are also not sufficiently described. Examiner could not find any expressed peptide from an intron, 5’ UTR, 3’UTR or lncRNA that has a different amino acid sequence in cancer cells vs noncancerous cells in the prior or contemporary art. Although upregulated micropeptides in cancer cells are known (see prior art rejections below), Examiner could not find a single example in the prior art of a micropeptide that has a different amino acid sequence, such as an amino acid substitution or a truncated form, in cancer cells versus non-cancerous cells. The Specification discloses a single example of an expressed transcript, ENST00000427352.1, that has a missense mutation in cancer cells vs noncancer cells. The Specification also discloses that ENST00000484282.1 is only expressed in tumor cells (page 18); however, the Specification does not disclose any changes in the sequence of the transcript in cancer vs noncancerous cells.
Although Applicants may argue that it is possible to screen for additional variant nORFs and polynucleotides, antibodies and small molecules that function as claimed, the court found in that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future polypeptides, antibodies, small molecules, and variant nORFs yet to be discovered that may function as claimed.
Given the lack of representative examples to support the full scope of the expression inhibitors encompassed by the claim, and lack of reasonable structure-function correlation with regards to the unknown sequences of polypeptides, antibodies and small molecules that provide can inhibit expression of known or unknown variant nORFs, the specification does not provide an adequate written description of molecules that inhibit expression of variant nORFs that function that is required to practice the claimed invention.
Dependent claims
Claims 3 and 45-48 do not limit the genus of “variant nORFs” or the genus of molecules and are insufficiently described for the reasons described above for claim 2.
Claim 4 limits the inhibitors to either an RNAi molecule of a polypeptide that is an antibody. For the reasons described above for claim 2, the genus of antibodies that function to reduce expression of a variant nORF are not sufficiently described. Regarding the RNAi molecules, although there is sufficient structure-function relationship between the sequence of the antisense molecule and its target, the genus of variant nORFs (i.e., the targets) are still not sufficiently described assuming a narrow interpretation of “variant nORF” meaning a change in the amino acid sequence in a cancer cell vs a noncancer cell.
Claim 50 recites the nORF has at least 80% identity to SEQ ID NO 1 or 2, which are both 90 amino acids in length. The genus of proteins having at least 80% identity to either SEQ ID NO 1 or 2 constitutes a genus of over 1041 different peptides. Applicant has described only a single nORF that encodes a peptide within that large genus. It is completely unknown which of those >1041 peptides actually function as the claimed “variant nORFs” and it is completely unknown what the structure of an inhibitor that reduces expression is.
Claim 52 recites three small molecules. The Specification discloses that the three compounds are predicted to bind the translated product of ENST00000427352.1. However, Applicant does not attempt to treat cancer cells with the compounds to determine if the compounds are capable of inhibiting expression of the translated product. Given that the compounds are predicted to bind the translation product of ENST00000427352.1, instead of some unknown transcriptional machinery that is responsible for the expression of ENST00000427352.1, the skilled artisan would not predict that the compounds could reduce expression of the translated product.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2-4 and 45-47 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Schwarz (Polycarpou-Scharz et al., Oncogene (2018), 37: 4750-4768).
As indicated above in paragraph 13, a “variant nORF” is interpreted as any open reading frame whose expression or amino acid sequence is associated with cancer cell vs a noncancer cell.
Regarding claims 2-4, Schwarz teaches Cancer-Associated Small Integral Membrane Open reading frame 1 (CASIMO1) is overexpressed in hormone-receptor-positive breast tumors (Abstract). Schwarz teaches the coding sequence for CASIMO1 is contained within a potential sORF (small ORF) within a putative noncoding RNA (ncRNA) (page 4751, ¶5). Schwarz teaches the expression levels of CASIMO1 are increased in breast tumor stages compared to normal breast tissue (page 4751, ¶1). Schwarz teaches the amino acid sequence of CASIMO1 differs from the amino acid sequence of an overlapping open reading frame SMIM22 (FIG 2B). Therefore, CASIMO1 is considered a variant nORF that is associated with cancer. Schwarz teaches inhibiting the expression of CASIMO1 using siRNAs (i.e., polynucleotides) (Fig 4), which reduces the proliferation rate of several cancer cells types (i.e., a method of treating cancer) (FIG. 6).
Regarding claim 45, Schwarz teaches CASIMO1 is 83 amino acids long (FIG 2B).
Regarding claims 46-47, Schwarz teaches a statistical analysis correlating an association between CASIMO1 expression and breast cancer (FIG 1E).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-4 and 45-48 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 2-4, 7-8 and 45-49 of copending Application No. 18267327.
Copending pending claim 1 recites A method of treating a cancer in a subject comprising administering to the subject an inhibitor that reduces expression of a nORF; wherein the subject has previously been identified with a sequence of the nORF and a cancer associated therewith, wherein the sequence of the nORF is distinct from a cORF of a gene, wherein the nORF is present in (i) an overlapping region of the cORF in an alternate reading frame, (ii) a 5' UTR of the cORF, (iii) a 3' UTR of the cORF, (iv) an intronic region of the cORF, (v) an intergenic region of the cORF, or (vi) a region not associated with the cORF or the gene, and wherein the nORF has increased expression relative to the nORF in a noncancerous cell. Because every ORF, and therefore nORF, is a variant of another by virtue of SNPs throughout the human genome in every ORF, “a variant nORF” is not patently distinct from the copending “nORF”. Copending claims 3-4 recites wherein the inhibitor comprises a small molecule, a polynucleotide [that] comprises a miRNA, an antisense RNA, an shRNA, or an siRNA, or a polypeptide [that] comprises an antibody or antigen- binding fragment thereof. Copending claim 45 recites wherein the encoded protein product of the nORF is less than about 100 amino acids. Copending claims 46-47 recite further comprising performing a statistical analysis between the nORF and the cancer [that] measures a positive or negative association between the nORF and the cancer. Copending claim 48 recites the cancer is selected from… lung adenocarcinoma and stomach adenocarcinoma.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CATHERINE KONOPKA whose telephone number is (571)272-0330. The examiner can normally be reached Mon - Fri 7- 4.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CATHERINE KONOPKA/Primary Examiner, Art Unit 1635
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