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 .
Claim Status
Currently, claims 1, 3-5, 7-10, 12-14, 16-21 are pending in the instant application. Claims 2, 6, 11, and 15 have been canceled. This action is written in response to applicant’s correspondence submitted 07/22/2026. All the amendments and arguments have been thoroughly reviewed but were found insufficient to place the instantly examined claims in condition for allowance. The following rejections are either newly presented, as necessitated by amendment, or are reiterated from the previous office action. Any rejections not reiterated in this action have been withdrawn as necessitated by applicant’s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. This action is FINAL.
Withdrawn Rejections
The rejection of claims 1, 3-5, 7-10, 12-14, 16-21 under 35 USC 112(a) is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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, 3-5, 7-10, 12-14, 16-21 are rejected under 35 U.S.C. 103 as being unpatentable over Elangovan (US20160220698 A1) in view of Fotin-Mleczek et al. (US20190241633A1). This rejection was previously presented and has been rewritten to address the amendment to the claims.
Elangovan teaches a method to enhance tissue regeneration and bone regeneration using compositions comprising modified RNA encoding BMP2 and PDGFB into cells for tissue engineering application (See para 19). Elangovan teaches the defect is a jaw bone and the administration of the compositions increased bone regeneration. Elangovan teaches the mammal is in need of periodontal regeneration (see para 9). Elangovan teaches a method of administering a composition comprising a RNA encoding PDGF or BMP (see para 9). Elangovan teaches administering in vivo an effective compositions to a tissue of a mammal (see claim 17 and 19 of ‘069). Elangovan teaches compositions comprising modified RNA encoding BMP2 into cells for tissue engineering application (See para 19).
With regard to claim 3-5 and 11-14, Elangovan teaches RNA molecules comprising 1-methyl pseudo uridine (see para 20). Elangovan teaches modified RNA is purified (see para 115).
With regard to claim 7-8 and 16-17, Elangovan teaches the RNA in complexed with a polymer nanoparticle, including lipids (see para 6, 51, 54).
With regard to claim 9, 18 and 21, Elangovan teaches the composition comprises a scaffold (see para 59-60 and para 86).
With regard to claim 19, Elangovan teaches administering single and different compositions to animals (see para 127).
Elangovan does not teach the sequence for PDGF or BMP2 and therefore does not teach SEQ ID NO 3 or SEQ ID NO 4.
However, it was known in the art to increase CG optimization of an RNA sequence for human codon usage and optimization for gene therapy (See para 30-31). Fotin-Mleczek teaches the sequences of the RNA, preferably mRNA may be modified and stabilized by modifying the G/C content, particularly increased compared to the G/C content of the wild type RNA (See para 138 and 149). Fotin-Mleczek teaches SEQ ID NO 40356 and SEQ ID NO 47442. SEQ ID NO 40356 is 90% identical to SEQ ID NO 4 and SEQ ID NO 47422 is 90% identical to SEQ ID NO 3. Fotin-Mleczek teaches BMP2 is SEQ ID NO 40356 (pg. 74) and PDGFB is SEQ ID NO 47442(pg253). Fotin-Mleczek teaches RNA molecules comprising 1-methyl pseudo uridine (see para 130). Fotin-Mleczek teaches modified RNA is purified (see instant claim 1 and para 330).Fotin-Mleczek teaches the RNA in complexed with a polymer nanoparticle, including lipids (see para 136).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to improve the composition and method of inducing regeneration of periodontal tissue using BMP2 and PDGF, as taught by Elangovan to include CG optimized mRNA sequences of BMP2 and PDGF, as taught by Fotin-Mleczek, to improve the method by Elangovan and include stabilized and optimized sequences. The ordinary artisan would have been motivated to improve the composition of using BMP2 and PGDF and method of using is taught by Elangovan with the composition and method of codon optimization of mRNA for gene therapy of BMP2 and PGDF as taught by Fotin-Mleczek because Fotin-Mleczek teaches an optimized mRNA sequence for gene therapy for BMP2 and PGDF comprising SEQ ID NO 40356 and 47442 that is 90% identical to SEQ ID NO 3 and SEQ ID NO 4. The ordinary artisan would have had a reasonable expectation of success that the use of modifying RNA sequence of BMP2 and PGDF-B including SEQ ID NO 3 and SEQ ID NO 4 could be used in the method of Elangovan et al. because Elangovan teaches using RNA comprising BMP2 and PGDF for inducing regeneration of periodontal disease and Fotin-Mleczek teach how to modify a sequence of BMP2 and PGDF for gene therapy and RNA compositions.
Because both Elangovan and Fotin-Mleczek et al. teach RNA compositions comprising lipid nanoparticles and modified 1-methyl-pseudouridine of BMP2 and PGDF for therapy, it would have been obvious to one skilled in the art to substitute one component, RNA of BMP2 and PGDF as taught by Elangovan with sequences of modified RNA sequences of BMP2 and PGDF, including sequences of SEQ ID NO 3 and 4 using the modification methods taught by Fotin-Mleczek, in order to achieve the predictable result of inducing regeneration of periodontal tissue.
Response to Arguments
The response traverses the rejection in the remarks mailed 07/22/2026 on pages 6-10. The response asserts based on the combination of references set forth by the Examiner, applicants assert that the rejection of the claims under 103 could only have been made with hindsight bias and ex post reasoning, which was previously traversed in the remarks mailed 01/21/2026. As addressed previously, in response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In the instant case, the test for obviousness 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 the combined teachings of Elangovan and Fotin-Mleczek render obvious the claimed invention.
The response further traverses the traversal made in the previous action mailed 01/21/2026. As addressed previously, the response asserts that in order for claims 1, 3-5, 7-10, 12-14 and 16-21 to render obvious the claims the combination of Elangovan and Fotin-Mleczek must teach or suggest each and every element of the claims. The response asserts there is nothing in the cited references that would motivate one of ordinary skill in the art to combine with a reasonable expectation of success the teaching of the references to produce the presently claimed invention. his response has been thoroughly reviewed but not found persuasive. As addressed in the previously, where 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 (see MPEP 2144). Based on the general knowledge available to one of ordinary skill in the art, the ordinary artisan would have been motivated to design and test the optimized sequences to obtain additional modified RNAs that function to induce regeneration of periodontal tissue or bone and identify RNA with improved properties, including SEQ ID NO 3 and SEQ ID NO 4. Because the art of Elangovan teaches modified RNA encoding PDGF or BMP2 to enhance tissue regeneration and bone regeneration, it would have been obvious to the ordinary artisan to generate modified RNA sequences encoding PDGF and BMP2 including SEQ ID NO3 and SEQ ID NO 4 based on the guidance provided by Fotin-Mleczek. Furthermore, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that was not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, generating nucleoside modified RNA from a sequence of SEQ ID NO 3 or SEQ ID NO4 to induce regeneration of periodontal tissue is within the technical grasp of an ordinary artisan based on the teaching of Fotin-Mleczek and Elangovan, and the general state of the art with regard to codon optimization including using known software tools and algorithmic strategies as asserted by applicants. Additionally the prior art demonstrates using modified RNA sequences to treat periodontal disease, including using modified BMP-2 sequences and PDGF-BB. While the prior art does not disclose the exact sequence, modification of RNA sequence for optimization is well known in the art and the prior art demonstrates that modified RNA of BMP-2 and PDGF-BB function to treat periodontal tissue. For example, Zhang (2019, Tissue Engineering Park A, 25(1-2):131-44) teaches modified BMP-2, Bhongsatiern (Chulalonkorn University These and dissertations, 2019) teaches modified PGDF-BB (see figure 1, pg 18-19) to treat periodontal regeneration, and Surisaeng (Chulalongkorn University Theses and dissertations, 2019) teaches nucleotide sequences of human PDGF-BB was designed and production of N1-methylpseuouridine mRNA encoding PDGF-BB was provided by Dr. Norbet Pardi (see pg 23) and teaches use of modified mRNA encoding PDGF-BB for periodontal regeneration. The art demonstrates the predictability of using modified PDGF-BB and BMP-2 RNA for treatment of periodontal disease. Therefore, absent secondary consideration such as evidence demonstrating unexpected results of SEQ ID NO 3 and SEQ ID NO 4, the ordinary artisan would have designed additional RNA sequences including SEQ ID NO 3 and SEQ ID NO 4 by methods well known in the optimize RNA sequences to induce regeneration of periodontal tissue, as demonstrated in the prior art.
The response asserts that MPEP 2143E articulates how to determine if a claim can be rejected as an obvious to try rational. The response asserts that neither Elangovan or Fotin-Mleczek teach or suggest a composition comprising the full length sequence of SEQ ID NO 3 or SEQ ID NO 4. The response asserts that the sequences set forth in SEQ ID NO 3 and SEQ ID NO 4 are optimized sequences that were optimized sequences designed for in vitro transcription. The response asserts that Fotin-Mleczek does not teach or suggest the specific optimized sequence. The response asserts that the general knowledge in the art of methods of optimization of sequences does not cure the deficiencies of Fotin-Mleczek as it provides methods of different ways to obtain optimized sequences but does not teach or suggest SEQ ID NO 3 or SEQ ID NO 4. This response has been reviewed but not found persuasive. Fotin-Mleczek was not cited to teach SEQ IDN O 3 and SEQ ID NO 4. Fotin-Mleczek was cites to teach that it was routine to optimized mRNA sequences including BMP-2 and PDGF-BB. Fotin-Mleczek teaches two sequences with 90% identity to SEQ ID NO 3 and SEQ ID NO 4 that have the same function as SEQ ID NO 3 and SEQ ID NO 4, demonstrating that optimization of RNA sequences has a predictable outcome. As previously addressed, where 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 (see MPEP 2144). Based on the general knowledge available to one of ordinary skill in the art, the ordinary artisan would have been motivated to design and test the optimized sequences to obtain additional modified RNAs that function to induce regeneration of periodontal tissue or bone and identify RNA with improved properties, including SEQ ID NO 3 and SEQ ID NO 4. Because the art of Elangovan teaches modified RNA encoding PDGF or BMP2 to enhance tissue regeneration and bone regeneration, it would have been obvious to the ordinary artisan to generate modified RNA sequences encoding PDGF and BMP2 including SEQ ID NO3 and SEQ ID NO 4 based on the guidance provided by Fotin-Mleczek. Furthermore, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that was not of innovation but of ordinary skill and common sense. See KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, generating nucleoside modified RNA from known sequences of BMP-2 and PDGF-BB to generate SEQ ID NO 3 or SEQ ID NO4 to induce regeneration of periodontal tissue is within the technical grasp of an ordinary artisan based on the teaching of Fotin-Mleczek and Elangovan, and the general state of the art with regard to codon optimization including using known software tools and algorithmic strategies as asserted by applicants. Additionally the prior art demonstrates that predictability of modifying BMP-2 and PDGF-BB to treat periodontal disease, as demonstrated by Zhang (2019, Tissue Engineering Park A, 25(1-2):131-44) teaches modified BMP-2, Bhongsatiern (Chulalonkorn University These and dissertations, 2019) teaches modified PGDF-BB (see figure 1, pg 18-19) to treat periodontal regeneration, and Surisaeng (Chulalongkorn University Theses and dissertations, 2019) teaches nucleotide sequences of human PDGF-BB was designed and production of N1-methylpseuouridine mRNA encoding PDGF-BB was provided by Dr. Norbet Pardi (see pg 23) and teaches use of modified mRNA encoding PDGF-BB for periodontal regeneration. Absent secondary consideration such as unexpected results of SEQ ID NO 3 and SEQ ID NO 4, the ordinary artisan would have designed additional RNA sequences including SEQ ID NO 3 and SEQ ID NO 4 by codon optimization to induce regeneration of periodontal tissue, as demonstrated in the prior art. This should not be construed as an invitation for providing evidence. Applicant is reminded of the timely submission of evidence as stated in MPEP 716.01.
The response asserts as an example Zhou (2013, exhibit A) demonstrates that routine codon optimization of Neurospora FRQ protein results in protein with increased stability but complete loss of function. The response further addresses Komar (2007) that describes alternating codon can have effects on translation kinetics and protein folding. The response asserts that although method of optimization of a known sequence are known to exist these methods do not result in predictable potential solutions. This response has been reviewed but not found persuasive. Zhou teaches routine codon optimization of Neurospora, which is a fungi, while the claimed composition is directed to human protein sequence and therefore is distinct. Zhou teaches that Neurospora uses non-optimal codon for proper protein folding, stability and function. Therefore it would be expected that routine codon optimization for FRQ in Neurospora would not function as expected because Neurospora use non-optimal codons. Additionally the teachings of Komar demonstrate silent SNP affecting function however Komar does not demonstrate that codon optimization results in unpredictable function in BMP-2 or PDGF-BB. There are no teachings that codon optimization of BMP-2 or PDGF-BB would result in unpredictable results. In fact there are many references that teach optimization of the RNA sequence of BMP-2 and PDGF-BB demonstrates the predictable result of treating periodontal disease (See Zhang, Bhongsatiern, Surisaeng, Elangovan, and Fotin-Mleczek).
The response asserts that the combination of Elangovan and Fotin-Mleczek does not meet the requirements that there was a finite number of identified, predictable potential solutions much less provide evidence that one of ordinary skill could have pursued the known potential solutions with a reasonable expectation of success. The response asserts that a person of skill would have generated an unknown number of optimized alternative and does not demonstrate a finite number of identified predictable optimized sequences. The response asserts that a person of skill in the art would not have selected and applied the appropriate optimization tools with appropriate input and constraints to arrive at the full length sequence of SEQ ID NO 3 and SEQ IDN O 4. The response asserts that it would require an unacceptable level of experimentation to arrive at SEQ ID NO 3 and SEQ ID NO 4. This response has been reviewed but not found persuasive. As addressed in MPEP 2143, E, the KSR requirement for a finite number of identified predictable solution places particular emphasis on predictability and the reasonable expectation of those of ordinary skill in the art. Additionally Example 3 is relevant to the current rejection. The board stated that that “when there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” KSR, 550 U.S. at 402-03, 82 USPQ2d at 1390. The Board noted that the problem facing those in the art was to isolate a specific nucleic acid, and there were a limited number of methods available to do so. The Board concluded that the skilled artisan would have had reason to try these methods with the reasonable expectation that at least one would be successful. Thus, isolating the specific nucleic acid molecule claimed was “the product not of innovation but of ordinary skill and common sense.” Id. In the instant case, the protein and nucleic acid sequence of BMP-2 and PDGF-BB was known in the art. Methods to modify and optimize RNA sequence was known in the art and the art demonstrates that codon optimization of BMP-2 and PDGF-BB results in predictable sequence that treats periodontal disease. The prior art teaches the parameters and objectives involved in the selection of codon optimization for modified RNA, as taught by Fotin-Mleczek. Moreover there are many internet web sites that provide free downloadable software to aid in the selection of optimized modified RNA drawn from genetic data. The prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid therapy to design modified optimized RNA. Specifically the prior art demonstrates optimized modified RNA of BMP-2 and PDGF-BB for treatment of periodontal disease and the ordinary artisan would have had a reasonable expectation of success of obtaining additional modified RNA sequences including SEQ IDNO 3 and SEQ IDN O 4 that function to treat periodontal disease. Thus, for the reasons provided above, the ordinary artisan would have designed additional optimized modified RNA molecules using the teachings in the art at the time the invention was made.
Conclusion
No claims are allowable.
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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/SARAE L BAUSCH/ Primary Examiner, Art Unit 1699
