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 .
Priority
This application was filed Feb. 21, 2020, and is a 371 application of PCT/US2020/019308, which claims benefit to the provisional application 62/821,377 filed on March 20, 2019, and is a CON of 16/281,988 filed Feb. 21, 2019, patented 11477970 and has provisional 62/653,092 filed April 5, 2018, and provisional 62/633,590 filed Feb. 21, 2018. Applicants claim for priority to a provisional application is acknowledged.
Claim Status
In the response filed on November 17, 2025, Applicants have amended claims 1, 4, 13, 17, 31, and 34, and canceled claims 2-3, 14-16, 18-22, 26-30, 32-33, 35-36, and 39-40.
Claims 1, 4-13, 17, 23-25, 31, 34 and 37-38 are currently under examination.
Withdrawn Objections & Rejections
Rejections and/or objections not reiterated from the previous office action are hereby withdrawn due to amendment. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The rejection of claims 1, 4-13, 17, 23-25, 31, 34 and 37-38 are under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of a transgenic nematode system for assessing a heterologous polygenic or monogenic phenotype for a human neurodegenerative disease, comprising and expressing a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence, wherein the first and second heterologous coding sequences are integrated into the host animal genome, and wherein expression of the first and second heterologous polypeptide coding sequences in the animal contribute to the heterologous phenotype, does not reasonably provide enablement for the following: any non-human animal transgenic system for assessing any heterologous disease phenotype, is withdrawn due to Applicants amendments (i.e. nematode) to the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-13, 17, 23-25, 31, 34, and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Hoener et al., (US 2003/0177507 A1, published 2003, cited IDS 2/2/2023, previously presented) in view of Redemann et al. ("Codon adaptation-based control of protein expression in C. elegans", Nature Methods, vol. 8, no. 3, 30; published 2011; cited IDS 2/2/2023, previously presented), Frokjaer-Jensen et al. (Cell, Vol. 166, pgs. 343-357, published 2016, cited IDS 2/2/2023, previously presented), Lee et al., (WO2014/172489A2, published 2014, cited IDS 2/2/2023, previously presented), and Harrington et al. (US 2003/0134421 A1, published 7/17/2003, cited IDS 2/2/2023, previously presented).
This rejection is repeated with regard to claims 1, 4-13, 17, 23-25, 31, 34 and 37-38 for the same reasons of record as set forth in the Official action mailed on August 15, 2025. A response to applicant' s traversal follows the reiterated rejection below.
Regarding claims 1, 4, 8, 11-12, 17, 31 and 38, Hoener discloses a non-human animal (i.e. nematode) transgenic system for assessing a heterologous disease phenotype (i.e. neurodegenerative disease)(see e.g. abstract, para. 18, 33-41, 47-48, 50-60, 64-65). Further, Hoener discloses a host animal comprising and expressing a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence, wherein the first and second heterologous polypeptide coding sequences are integrated into the host genome, wherein at least one of the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence comprises one or more mutations in the heterologous polypeptide coding sequence as compared to a wildtype reference sequence (see e.g. para. 51, page 9, fig. 3) resulting in at least one amino acid change when the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence is expressed (see e.g. paras 43-53, and para. 165-166, claim 8). Further, Hoener discloses one or more mutations in the human gene exon coding sequence as compared to a wildtype reference sequence (see e.g. page 9, figs. 1-5) resulting in at least one amino acid change when the first human gene or the second human gene is expressed in the host animal (see e.g. fig. 3-5). Hoener discloses wherein expression of the first and second heterologous polypeptide coding sequence contribute to the heterologous human disease phenotype (see e.g. para. 33-43, claims 1-20, page 11-13, fig. 3-12). Further, Hoener discloses wherein the heterologous exon coding sequences interspersed with artificial host intron sequences optimized for expression in the host animal (see e.g. page 9, para. 124-125, fig.1-3).
However, Hoener is silent regarding wherein at least one of the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence is a chimeric heterologous polypeptide coding sequence comprising heterologous exon coding sequences interspersed with artificial host intron sequences optimized for expression in the host.
However, the prior art of Redemann discloses heterologous chimeric C. elegans genes interspersed with artificial host intron sequences optimized for expression in the host of synthetic C. elegans gpr-1 constructs which contain three artificial introns, where the transgene is optimized for a desired expression level (see e.g. page 250-251, methods, first page, first column, first paragraph).
Accordingly, it would have been obvious, to a person of ordinary skill in the art to have modified the first or second heterologous polypeptide coding sequences comprising exon coding sequences, and a nematode host (as taught by Hoener), with a heterologous C. elegans gene interspersed with artificial C. elegans intron sequences optimized for expression in a C. elegans (as taught by Redemann) because Redemann discloses a superior transgenic system which provides the benefit of using artificial nematode intron sequences in a transgene to optimize expression of the transgene and prevent under-expression or over-expression (see e.g. page 250). Incorporating the superior nematode system would have led to predictable results with a reasonable expectation of success because both Hoener and Redemann teach using nematodes as a model organism for expressing genes. Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 5-7, Hoener discloses wherein the first heterologous coding sequence and/or the second heterologous coding sequence has been knocked-out (see e.g. para. 12-15, 60, 167, 205, fig. 2). Further, Hoener discloses an isolated nucleic acid molecule which encodes the C. elegans Parkin gene, to homologs and fragments of this molecule, and to a polypeptide or protein which is encoded by such a nucleic acid molecule (see e.g. page 3), which reads on the host gene ortholog.
Although Hoener does not explicitly state wherein at least one of the first heterologous coding sequence or the second heterologous coding sequence replaced an entire host gene ortholog at a native locus. Nevertheless, the prior art of Frokjaer-Jensen et al., disclose “a pervasive non-coding DNA feature in Caenorhabditis elegans, characterized by 10-basepair periodic An/Tn-clusters (PATCs), can license transgenes for germline expression within repressive chromatin domains and among endogenous genes, intron length and PATC-character undergo dramatic changes as orthologs move from active to repressive chromatin over evolutionary time” (See e.g. abstract, fig. 7).
Regarding claims 5-7, and 34, Frokjaer-Jensen et al., discloses “unique C. elegans and C. briggsae ortholog pairs and determined their PATC content as a function of genomic location and expression in the germline (Figure 7C)”(see e.g. page 9).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Hoener with the orthologs as taught Frokjaer-Jensen and have the first and second heterologous coding sequences individually replaced an entire host gene ortholog at a native locus because Frokjaer-Jensen discloses that periodic An/Tn clusters (PATCs) form the basis of a cellular immune system (see e.g. page 1-2). Frokjaer-Jensen disclose that orthologs pairs that remain on arms have longer introns (Figure 7D) and higher PATC frequency (Figure 7E) compared to ortholog pairs that remained at a central location over evolution (see e.g. page 9). Further, Frokjaer-Jensen discloses that the periodic PATCs are found within introns or in intergenic regions and can promote germline expression of transgenes in repressive environments (see e.g. page 1-2, 9-10). A person of ordinary skill in the art would have done so with a reasonable expectation of success because Hoener discloses homologous genes from other organisms (i.e. including orthologs)(See e.g. page 3). Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 9, and 25, as discussed above, Hoener discloses a host animal comprising and expressing a first heterologous polypeptide coding sequence and a second heterologous polypeptide coding sequence, wherein the first and second heterologous polypeptide coding sequences are integrated into the host genome, wherein at least one of the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence comprises one or more mutations in the heterologous polypeptide coding sequence as compared to a wildtype reference sequence (see e.g. para. 51, page 9, fig. 3)
Hoener does not explicitly state wherein the system further comprising and expressing one or more additional heterologous polypeptide coding sequence that contribute to the heterologous disease phenotype.
However, the prior art of Lee discloses any heterologous polynucleotide coding sequence of interest may be integrated into the targeted genomic locus, where at least 1-6 polynucleotides may be used, where the endogenous nucleic acid sequence is deleted and the exogenous nucleic acid sequence is introduced, where the polynucleotide is a mutant protein which is a disease allele. (see e.g. para. 304-306, and 3241), corresponding to the claim limitation of expressing one or more heterologous polypeptide coding sequences that contributes to the heterologous phenotype.
Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the transgenic system as taught by Hoener with one or more heterologous polypeptide coding sequences that contributes to the heterologous phenotype as taught by Lee because Lee discloses a superior transgenic system which provides the benefit of using 1-6 heterologous polynucleotide sequences to produce a disease phenotype which is the result of multiple genes (see Lee e.g. para. 3241). Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 10, 23-24 and 37, Hoener discloses wherein the mutation corresponds to a human disease gene clinical variant (see e.g. para. 10-17) and wherein the first and second heterologous polypeptide coding sequences comprise human exon coding sequences (i.e. human a-synuclein gene A53T)(see e.g. paras, 16, 51-52). Further, Hoener discloses wherein the one or more mutations corresponds to a human disease gene clinical variant (i.e. the A53T mutation is used, where A53T mutation in the a-synuclein gene lead to hereditary form of Parkinson's disease)(see e.g. para. 161).
Regarding claims 13, Hoener discloses an invention that relates to the polypeptides or proteins which are encoded by the exemplified nucleic acid molecules, in particular to a C. elegans Parkin having the amino acid sequence given in FIG. 3 and to polypeptides or proteins which are derived therefrom (see e.g. para. 120, fig. 3). Further, Hoener discloses the size of the descendants and number of the eggs which were laid by Parkin KO1 worms (i.e. one heterologous polypeptide coding sequences)(see e.g. fig. 9).
Hoener does not explicitly state wherein the host animal comprises and expresses 3 to 15 heterologous polypeptide coding sequences.
Nevertheless, the prior art of Harrington et al. discloses that the ordinarily skilled artisan will readily understand that insertional mutagens can comprise one or more desired proteins or peptides encoded by a gene or a portion of a gene as the insertional mutagens (see e.g. abstract, page 24).
Furthermore, a person of ordinary skill in the arts could have arrived at the number of 3 to 15 heterologous polypeptide coding sequences by routine optimization and the disclosure does not point to a criticality in the number of heterologous polypeptide coding sequences that the host animal comprises and expresses.
In regards to routine optimization, MPEP 2144.05(II)(A) states, “generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. ‘[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (‘It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.’)”.
Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the transgenic system as taught by Hoener with the host animal comprising and expressing 3 to 15 heterologous polypeptide coding sequences as taught by Harrington because Hoener and Harrington both disclose methods for inserting mutants into a transgenic system, as discussed above. A person of ordinary skill in the art would have a reasonable expectation of success because both Hoener and Harrington disclose introducing one or more mutations in the heterologous exon coding sequence resulting in at least one amino acid change for providing a transgenic test nematode and that the mutation corresponds to a human disease gene clinical variant resulting in a desired phenotype (see e.g. para. 339). Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Response to Traversal:
Applicant argues that the art does not discloses and teach a single heterologous sequences integrated and expressed, not two or more (Remarks, page 8). Applicant argues that Hoener does not disclose a transgenic nematode with one heterologous gene, a first and second integrated, and expressing heterologous sequence as recited in the claims that drive the phenotype being assessed (Remarks, page 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, as discussed above, prior art of Redemann is cited for disclosing at least one of the first heterologous polypeptide coding sequence or the second heterologous polypeptide coding sequence is a chimeric heterologous polypeptide coding sequence comprising heterologous exon coding sequences interspersed with artificial host intron sequences optimized for expression in the host (see e.g. page 250-251, methods, first page, first column, first paragraph).
In response to Applicants arguments, the test for obviousness is not whether the features of a secondary reference maybe bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413,208 USPQ 871 (CCPA 1981). In the instant case, it would have been obvious to a person of ordinary skill in the art to have modified the first or second heterologous polypeptide coding sequences comprising exon coding sequences, and a nematode host (as taught by Hoener), with a heterologous C. elegans gene interspersed with artificial C. elegans intron sequences optimized for expression in a C. elegans (as taught by Redemann) because Redemann discloses a superior transgenic system which provides the benefit of using artificial nematode intron sequences in a transgene to optimize expression of the transgene and prevent under-expression or over-expression (see e.g. page 250). Incorporating the superior nematode system would have led to predictable results with a reasonable expectation of success because both Hoener and Redemann teach using nematodes as a model organism for expressing genes. Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
The MPEP 2123 (I) states that patents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Applicant is reminded that preferred embodiments are not the only teaching of a reference. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). As discussed above, Hoener discloses wherein the mutation corresponds to a human disease gene clinical variant (see e.g. para. 10-17) and wherein the first and second heterologous polypeptide coding sequences comprise human exon coding sequences (i.e. human a-synuclein gene A53T)(see e.g. paras, 16, 51-52). Further, Hoener discloses wherein the one or more mutations corresponds to a human disease gene clinical variant (i.e. the A53T mutation is used, where A53T mutation in the a-synuclein gene lead to hereditary form of Parkinson's disease)(see e.g. para. 161). Further, Hoener discloses that “a mutated gene product is expressed, one or more mutation(s) is/are present, where appropriate in addition to mutations in regulatory regions, in the coding region of the gene which is homologous or heterologous with respect to the target organism, which mutation(s) lead(s) to a change in the amino acid sequence of the translated gene product as compared with the amino acid sequence of the native gene product”. As discussed above, the prior art of Lee discloses any heterologous polynucleotide coding sequence of interest may be integrated into the targeted genomic locus, where at least 1-6 polynucleotides may be used, where the endogenous nucleic acid sequence is deleted and the exogenous nucleic acid sequence is introduced, where the polynucleotide is a mutant protein which is a disease allele. (see e.g. para. 304-306, and 3241), corresponding to the claim limitation of expressing one or more heterologous polypeptide coding sequences that contributes to the heterologous phenotype. Accordingly, it would have been obvious to a person of ordinary skill in the art to have modified the transgenic system as taught by Hoener with one or more heterologous polypeptide coding sequences that contributes to the heterologous phenotype as taught by Lee because Lee discloses a superior transgenic system which provides the benefit of using 1-6 heterologous polynucleotide sequences to produce a disease phenotype which is the result of multiple genes (see Lee e.g. para. 3241). Furthermore, an artisan of ordinary skill in the art of (i.e. gene editing) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Applicant argues that the prior art of Redemann et al. teaches certain heterologous chimeric C. elegans genes, that Frokjaer-Jensen et al. teach replacing certain host genes with an ortholog, that Lee et al. teach certain heterologous coding sequence may be integrated in the target genomic locus, or that Harrington et al. teach insertional mutagens, do not cure the fatal deficiencies of the primary reference as to the rejected claims (Remarks, page 9).
Applicant arguments are acknowledged, have been fully considered, and have been deemed unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a single heterologous sequences integrated and expressed) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In the instant case, Applicant argues that the prior art does not have “disclosure for a first and second integrated and expressing heterologous sequence as recited in the claims that drive the phenotype being assessed”. It is noted that the breadth of the claim is to any heterologous polygenic or monogenic phenotype (see claim 1). Therefore, it is unclear what phenotype Applicant is referring too.
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references (i.e. Redemann et al., Frokjaer-Jensen et al., that Lee et al. and Harrington et al.).
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Conclusion
No claim is allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
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JOSEPHINE GONZALES
Examiner
Art Unit 1631
/JOSEPHINE GONZALES/ Examiner, Art Unit 1631
/JAMES D SCHULTZ/ Supervisory Patent Examiner, Art Unit 1631