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 .
Status of Claims
Claims 1, 3-7, 9-14, and 18-20 are pending and under exam. Claims 2, 8 and 15-17 are cancelled.
WITHDRAWN REJECTIONS AND OBJECTIONS
Claim Objections
Claims 5-10, and 12-17 were objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim should refer to other claims in the alternative only, and/or, cannot depend from any other multiple dependent claim. The objection is withdrawn following claim amendments.
Claim Rejections - 35 USC § 112
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 15-17 were rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Claims 15-17 described use of a composition of claims 10 or 11 for a specific use, without reciting active steps. The rejection is withdrawn following cancellation of the claims.
Claim Rejections - 35 USC § 103
Claims 1, 3-4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Soria-Juan et al (Front Immunol. 2019 Jun 4; hereinafter "Soria-Juan;" PTO-892 of 02/24/2026) in view of Delenda et al (J Gene Med. 2004 Feb; hereinafter "Delenda;" See PTO-892 of 02/24/2026).
The rejection is withdrawn following claim amendments.
NEW REJECTIONS NECESSITATED BY THE CLAIM AMENDMENTS
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.
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.
Claim 1, 3-4, 10-14 and 19-20 is rejected under 35 U.S.C. 103 as being unpatentable over Soria-Juan et al (Front Immunol. 2019 Jun 4; hereinafter "Soria-Juan;" PTO-892 of 02/24/2026) in view of Delenda et al (J Gene Med. 2004 Feb; hereinafter "Delenda;" See PTO-892 of 02/24/2026), and further in view of Inouye et al (Protein Expr Purif. 2015 May; hereinafter "Inouye;" See PTO-892); GenBank U59105, NM_003467; first available 1988; hereinafter "GenBank;" See PTO-892 of 02/24/2026) and Kotenko et al (EMBO J. 1997 Oct 1; hereinafter "Kotenko;" See PTO-892 of 02/24/2026).
Regarding claims 1, 3-4, 10-13 and 19-20: Soria-Juan was directed to developing and evaluating a cost-effective, safe and personalized cell therapy approach for critical limb ischemia in Type 2 diabetes patients. Soria-Juan taught that “Targeting the CXCL12 and C-X-C chemokine receptor type 4 (CXCR-4) may improve the cell migration capacity of transplanted MSCs, and CXCL12 is also highly expressed in injured tissues and contributes to the recruitment of CXR4-positive cells. As a small proportion of MSCs express CXCR4 in culture, their capacity to migrate, and to respond to homing signals in damaged tissue may be reduced. Therefore, targeting CXCR4 may improve the migratory and therapeutic effects of MSCs. Within this context, we propose using MSCs modified to overexpress CXR4 and IL10 and/or IL7 (Generation 3 MSCs). Expression of the CXCR4 receptor will increase the migration of MSCs toward the inflammatory focus, while coexpression of the anti-inflammatory cytokine interleukin 10 (IL-10) and/or the anti-infectious cytokine interleukin 7 (IL-7) will increase the anti-inflammatory effect (IL-10) and even the anti-infective effect (IL-7).” (See Soria-Juan p. 12, col. 2, para 2). As such Soria-Juan established the desirability of co-expression of CXCR4 and IL-10 in MSC (claims 12, 19). It is also noted that Table 1 of Soria-Juan taught various sources of MSC as required by claim 13. It is also noted that Soria-Juan taught “use of MSCs as a cell-based therapy for CLI, recent data suggest that the therapeutic effects of these cells in ischemic pathologies are due to the secretion of angiogenic molecules to bioactive levels and their ability to restore the microenvironment of the damaged area” (See Soria-Juan, p. 8, col. 1, last para), reading on the pharmaceutical composition of claim 20.
Delenda was directed to the use of lentiviral vectors (claim 11) for delivery of transgenes of interest. Delenda taught “co-expressing the transgene of interest with a reporter gene in order to follow the expression in bulk cell population” (Delenda S132, col. 2, last para). Delenda taught that “Transfer vector genomes contain all the cis-active sequences needed for packaging (ψ), reverse transcription (primer binding site, LTRs), integration (attL and attR integration sites) and transcription (5′-LTR or internal heterologous promoter), as well as the transgene of interest.“ (Delenda S128, col. 1, last para – col. 2, first para). It is further noted that Delenda taught codon optimization of transgenes (as required by claim 2) (See Delenda Figure 2). Delenda further taught “The improvement of transgene expression has also been facilitated by the addition of elements that act post-transcriptionally. The insertion of the post-transcriptional regulatory element (PRE) of the woodchuck (WPRE – as required by claims 3 and 4) or human (HPRE) hepatitis B viruses (HBVs) has substantially increased the levels of expression from HIV-1-derived vectors in a transgene-, promoter- and vector-independent manner.” (Delenda S128, col. 2, para 4). As such the vector delivery systems of Delenda are interpreted to read on pharmaceutical compositions as required by claim 14.
Further, Inouye taught a technique of codon optimization using “design rule for preparing codon-optimized genes for expression it in mammalian cells by selection of only preferentially used human codons” (See Inouye, p. 47, col. 1, para 1). It is also submitted that the sequences of CXCR4 and IL10 were previously known (See Kotenko and GenBank). The resulting nucleotide sequences (SEQ ID NO: 1 and SEQ ID NO: 3); being codon optimized variants encoding the same known proteins would have been predictable products of routine optimization and therefore obvious, absent evidence of unexpected results.
A person of ordinary skill in the art in reading Soria-Juan would have realized importance of co-expression of CXCR4 and IL10 in MSC to improve migration and anti-inflammatory activity and would have been motivated to create a genetic cassette capable of co-expressing these two proteins to achieve the same functional outcome. Delenda taught that lentiviral vectors and other mammalian expression systems routinely included promoters and other elements such as WPRE elements and codon-optimization of transgenes themselves to achieve a stable and high-level transgene expression, as such the construction of two coding sequences is a predictable and well-known practice in the art. It would have been routine for a skilled artisan to employ bicistronic strategies as described in Delenda to co-express CXCR4 and IL-10 in a single vector, given the required therapeutic effect of Soria-Juan. The resulting construct would have been predictable and within routine capabilities of a skilled artisan.
Claim 5-7 and 18 is rejected under 35 U.S.C. 103 as being unpatentable over Soria-Juan et al (Front Immunol. 2019 Jun 4; hereinafter "Soria-Juan;" PTO-892 of 02/24/2026) in view of Delenda et al (J Gene Med. 2004 Feb; hereinafter "Delenda;" See PTO-892 of 02/24/2026), and further in view of Inouye et al (Protein Expr Purif. 2015 May; hereinafter "Inouye;" See PTO-892); GenBank U59105, NM_003467; first available 1988; hereinafter "GenBank;" See PTO-892 of 02/24/2026); Kotenko et al (EMBO J. 1997 Oct 1; hereinafter "Kotenko;" See PTO-892 of 02/24/2026) and further in view of Chinnasamy et al (Virol J. 2006 Mar 15; hereinafter “Chinnasamy ;” See PTO-892).
Regarding claim 5-7, and 18: It is submitted that the prior art did not teach PGK promoter or 2A peptide for expression of two proteins. However, PGK promoters and 2A peptide are routinely used in the art of gene delivery and heterogenous protein expression. For example, Chinnasamy taught that two or three transgenes can be expressed in HIV-1 based lentiviral vector in a bicistronic and tricistronic self-inactivating format employing foot-and-mouth disease virus (FMDV) cleavage factor 2A. (See Chinnasamy Abstract). Further Chinnasamy taught that “[m]ultigene lentiviral vectors were constructed based on the previously described self-inactivating (SIN) lentiviral vector backbone with central polypurine tract (cPPT) and woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) in which transgene(s) are expressed under the control of the human PGK promoter.” (See Chinnasamy p. 2, col. 2, para 4).
In view of these teachings and the general knowledge in the art, it would have been obvious to a person of ordinary skill in the art to incorporate a PGK promoter and a 2A cleavage peptide into the claimed construct in order to obtain reliable transgene expression and multicistronic expression of the desired gene products. Such modification merely involves the application of known vector design elements according to their established functions and would have yielded predictable results. Absent evidence demonstrating criticality or unexpected results attributable to the claimed arrangement, the selection and use of a PGK promoter and a 2A cleavage peptide would have been an obvious matter of routine optimization and design choice.
Claim 9 are rejected under 35 U.S.C. 103 as being unpatentable over Soria-Juan et al (Front Immunol. 2019 Jun 4; hereinafter "Soria-Juan;" PTO-892) in view of Delenda et al (J Gene Med. 2004 Feb; hereinafter "Delenda;" See PTO-892), and further in view of Inouye et al (Protein Expr Purif. 2015 May; hereinafter "Inouye;" See PTO-892); GenBank U59105, NM_003467; first available 1988; hereinafter "GenBank;" See PTO-892); Kotenko et al (EMBO J. 1997 Oct 1; hereinafter "Kotenko;" See PTO-892) and Chinnasamy et al (Virol J. 2006 Mar 15; hereinafter “Chinnasamy ;” See PTO-892) further as evidenced by Kim (WO2020237104A1; published 2020-11-26; See PTO-892).
It is submitted that the prior art did not teach PGK promoter or 2A peptide for expression of two proteins. However, PGK promoters and 2A peptide are routinely used in the art of gene delivery and heterogenous protein expression. For example, Chinnasamy taught that two or three transgenes can be expressed in HIV-1 based lentiviral vector in a bicistronic and tricistronic self-inactivating format employing foot-and-mouth disease virus (FMDV) cleavage factor 2A. (See Chinnasamy Abstract). Further Chinnasamy taught that “[m]ultigene lentiviral vectors were constructed based on the previously described self-inactivating (SIN) lentiviral vector backbone with central polypurine tract (cPPT) and woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) in which transgene(s) are expressed under the control of the human PGK promoter.” (See Chinnasamy p. 2, col. 2, para 4).
In view of these teachings and the general knowledge in the art, it would have been obvious to a person of ordinary skill in the art to incorporate a PGK promoter and a 2A cleavage peptide into the claimed construct in order to obtain reliable transgene expression and multicistronic expression of the desired gene products. Such modification merely involves the application of known vector design elements according to their established functions and would have yielded predictable results. Absent evidence demonstrating criticality or unexpected results attributable to the claimed arrangement, the selection and use of a PGK promoter and a 2A cleavage peptide would have been an obvious matter of routine optimization and design choice. It is noted that while the cited references did not explicitly teach the sequence of SEQ ID NO: 2, the sequence was well known, as evidenced by Kim. Kim disclosed a SEQ ID NO: 5 which is 100% percent identical to 2A sequence.
Claim Rejections - 35 USC § 112
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.
Claim 7 and 9 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 recite a "functional variant" of PGK promoter. The specification does not reasonably convey to one of ordinary skill in the art that Applicant was in possession, as of the filing date, of the full scope of polypeptides encompassed by the term "functional variant." While the specification discloses a PGK promoter, the claims encompass an indeterminate number of sequence variants defined solely by their ability to perform a recited function, namely promoting transcription of a sequence. The specification does not identify sufficient structural features common to the claimed genus of functional variants, nor does it provide a representative number of species that would permit one of ordinary skill in the art to recognize the boundaries of the claimed genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the applicant [inventor] has made a generic invention that achieves the claimed result and do so by showing that the applicant [inventor] has invented species sufficient to support a claim to the functionally-defined genus. (See MPEP 2161.01 I). Accordingly, the disclosure does not demonstrate possession of the full scope of the claimed functional variants.
Response to Arguments: Applicant argued that the claimed non-native codon-optimized CXCR4 and IL-10 sequences produce unexpected results, including enhanced MSC migration, immunosuppressive activity and anti-inflammatory effects. However, these arguments are not persuasive. The cited data compare MSCs transduced with CXCR4 and IL10 constructs with wildtype MSCs and demonstrates biological activities that would have been expected increased expression of CXCR4 and IL-10, namely enhanced migration toward CXCL12/SDF-1 and increased anti-inflammatory activity. The evidence does not establish that the claimed codon optimized sequences provide results that are unexpected relative to the closest prior art, including known CXCR4 and IL1-0 coding sequences or other codon optimized variants.
Furthermore, codon optimization was a well-known technique in the art to improve transgene expression in mammalian cells, as evidenced by Delenda and Inouye. To the extent the claimed sequences result in increased expression, stability, or protein production, such results are expected consequences of codon optimization and do not constitute evidence of unexpected results. Applicant had not provided comparative evidence demonstrating that the particular claimed codon-optimized sequences yield a surprising property or an improvement in kind rather than degree, over what would have been reasonably expected by a person of ordinary skill in the art. Accordingly the evidence is insufficient to overcome the prima facie case of obviousness.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M. Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JAGAMYA NMN VIJAYARAGHAVAN/Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
Prosecution Insights