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 .
Status of Application/Amendments/Claims
Applicant’s response filed on 9/18/2025 has been considered. It is acknowledged that the office action dated 3/18/2025 incorrectly contained the statement “this action is made final” in the conclusion section. However, the present action is made final as all claims have been twice rejected. No claims have been amended. Claims 15, 17, 26-33 are pending. Claims 27, 29 and 31 are currently withdrawn without traverse from further consideration pursuant to 37 CFR 1.142 (b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 15, 17, 26, 28, 30 and 32-33 are the subject of the present Official action. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
Applicant’s claim for the benefit of a prior-filed application KR10-2016-0143519 and PCT/KR2017/012136 filed on 10/31/2016 and 10/31/2017, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 10/31/2016.
Maintained 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 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.
Claims 15, 17, 26 and 33 stand rejected under 35 U.S.C. 103 as being unpatentable over Goins et al. "Gene therapy for the treatment of chronic peripheral nervous system pain." Neurobiology of disease 48.2 (2012): 255-270 (hereinafter Goins, reference of record) in view of Tavares et al. "Gene therapy for chronic pain management." Gene Therapy-Tools and Potential Applications. IntechOpen, 2013 (hereinafter Tavares, reference of record) as evidenced by Levicoff et al. "Safety assessment of intradiscal gene therapy II: effect of dosing and vector choice." Spine 33.14 (2008): 1509-1516 (hereinafter Levicoff, reference of record). This rejection is maintained for the same reasons of record as outlined in the official action dated 3/18/2025. A reply to applicants’ traversal is found below.
Claim 15: Goins describes gene therapy approaches for the treatment of chronic peripheral nervous system pain (Goins, abstract). Goins describes viral based vectors and approaches for delivering neurotrophin genes (GDNF), neurotransmitter genes (GAD65) and immune modulatory genes (IL-10) for pain treatment, corresponding to the elected genes of claim 1 (Goins, table 2 sections A-C). Goins describes viral vector systems which can express multiple genes and the use of multiple therapeutic genes in combination (Goins, sections: non-viral and viral vectors for the treatment of chronic pain pg 258 and clinical gene therapy trials for pain pg 266). In table 1, Goins lists suitable gene delivery vectors including adenovirus, adeno-associated virus (AAV), herpes simplex virus and lentivirus among others, corresponding to the vectors described in claim 3 (Goins, table 1). In Fig 1, Goins diagrams various viral vector constructs including information regarding total genome size, the position of relevant genes, transcriptional control elements and viral sequences involved in genome replication and packaging. Goins states that the delivery of neurotrophin genes such as GDNF was found to be beneficial for the treatment of chronic pain by lowering levels of cytokine synthesis along with promoting growth (Goins, pg 263, section: Neurophrophic/growth factor gene therapy). Goins states that the delivery of neurotransmitter genes such as GAD65 was found to inhibit neuropathic pain signaling in the dorsal horn of the spinal cord (Goins, pg 265 section: neurotransmitter-based gene therapy). Furthermore, Goins states that the delivery of immune modulatory genes such as IL-10 can suppress the expression of proinflammatory cytokines produced by activated glial cells and antagonize the signaling pathway activated by these cytokines (Goins, pg 265 section: Immuno-modulatory molecule gene therapy). In table 2, Goins cites specific references which provided detailed embodiments for each gene therapy approach for the treatment of chronic pain. Goins describes administration routes via intrathecal injection into the spinal cord (Table 2, cited as “i.t. spinal cord”). Although Goins describes administration routes via intrathecal injection into the spinal cord, Goins does not expressly describe epidural injection. Goins does not expressly describe the specific gene combinations contained in a first, second or third vector as described in newly added claim 15.
Claim 17: Goins describes approaches for the treatment of chronic peripheral nervous system pain (Goins, abstract). Goins describes various chronic pain states including nociceptive pain and cancer pain (Goins, pg 256).
Claim 26: Goins describes the delivery of neurotransmitter genes such as GAD65 which were found to inhibit neuropathic pain signaling in the dorsal horn of the spinal cord (Goins, pg 265 section: neurotransmitter-based gene therapy).
Claim 15: Reliable methods exist to combine transgenes into single or multiple vectors for targeted expression for similar therapeutic purposes. For example, Tavares describes gene therapy approaches for managing chronic pain (Tavares, intro). Tavares identifies the physiological pain transmission pathways, genes and neuropathic pain models used for treating chronic pain via gene therapy (Tavares, Fig 1 and Table 1). Like Goins, Tavares identifies GAD, IL-10 and GDNF as transgenes useful in managing chronic pain.
It would have been prima facie obvious to one of ordinary skill in the art to formulate different transgene combinations of GAD, IL-10 and GDNF as single or multiple vectors for the treatment of chronic pain. It is prima facie obvious to combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, see MPEP 2144.06. The idea of combining GAD, IL-10 and GDNF into a single vector or combinations thereof flows logically from there having been individually taught in the prior art. Thus, it would have been a matter of combining known prior art elements for one of ordinary skill to arrive at the gene and vector combinations described in claim 15. One would be motivated to make this combination since GAD, IL-10 and GDNF are all known to be useful in managing chronic pain as shown by both Goins and Tavares. One would have a reasonable expectation of success given that the incorporation of multiple transgenes in a single vector is considered routine in the art and there exist predictable methods for constructing such gene expression constructs.
Claim 15: Levicoff provides a clinical, biochemical and histological analysis of AAV vectors encoding various anabolic cytokines and marker genes which are administered via epidural injection into New Zealand white rabbis (Levicoff, abstract). Levicoff shows that “properly dosed and directed gene therapy via epidural injection is both safe and potentially efficacious” (Levicoff, Abstract-conclusion). Levicoff shows that epidural injection resulted in only a mild inflammatory response (Levicoff, Results – Histology).
It would have been prima facie obvious to one of ordinary skill in the art to administer the therapeutic AAV vector as described by Goins in view of Tavares via epidural injection as described by Levicoff. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to use epidural injection instead of intrathecal injection as taught by Goins. One would be motivated to make this combination since Levicoff shows that epidural injection results in only a mild inflammatory response. One would have a reasonable expectation of success given the close physical proximity of intrathecal and epidural injection sites (i.e. both are administration techniques into the spinal column). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 15, 17, 23-24, 26 and 33 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing that Tavares does not teach reliable methods to combine transgenes into a single or multiple vectors for targeted expression since Table 1 only lists single gene products.
This argument has been fully considered, but was not found persuasive since Goins describes viral vector systems which can express multiple genes and the use of multiple therapeutic genes in combination (Goins, sections: non-viral and viral vectors for the treatment of chronic pain pg 258 and clinical gene therapy trials for pain pg 266). One cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references, see MPEP 2145. Tavares is introduced as prior art in combination with Goins to show that it is prima facie obvious to combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, see MPEP 2144.06. The idea of combining GAD, IL-10 and GDNF into a single vector or combinations thereof flows logically from there having been individually taught in the prior art. One would be motivated to make this combination since GAD, IL-10 and GDNF are all known to be useful in managing chronic pain as shown by both Goins and Tavares.
Applicant further argues that Levicoff teaches away from employing AAV vectors to deliver therapeutic genes to epidural spaces (Levicoff, Fig 2 and 7).
These arguments have been fully considered, but are not found persuasive. Teaching away requires the prior art to criticize, discredit, or otherwise discourage the claimed solution, see MPEP § 2141.02(VI): “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed.” Since the prior art clearly does not do this, this argument is unconvincing. With respect to Levicoff, a closer reading of the text concludes with Levicoff’s finding that “properly dosed and directed gene therapy via epidural injection is both safe and potentially efficacious” (Levicoff, Abstract-conclusion). Figure 7 shows that there is no transgene expression across the blood-brain barrier contrary to applicants’ arguments. Furthermore, Goins describes administration routes via intrathecal injection into the spinal cord, which is very closely related to epidural injections (Table 2, cited as “i.t. spinal cord”).
Claims 28, 30 and 32 stand rejected under 35 U.S.C. 103 as being unpatentable over Goins (supra), Tavares (supra) and Levicoff (supra) as applied to claims 15, 17, 26 and 33 above in further view of Gao et al. "UpGene: application of a web‐based DNA codon optimization algorithm." Biotechnology progress 20.2 (2004): 443-448 (hereinafter Gao, reference of record), Goodman et al. "Synthesis and characterization of rat interleukin-10 (IL-10) cDNA clones from the RNA of cultured OX8− OX22− thoracic duct T cells." Biochemical and Biophysical Research Communications 189.1 (1992): 1-7 (hereinafter Goodman, for disclosing “IL-10” NM-012854), Airavaara et al. "Identification of novel GDNF isoforms and cis-antisense GDNFOS gene and their regulation in human middle temporal gyrus of Alzheimer disease." Journal of Biological Chemistry 286.52 (2011): 45093-45102 (hereinafter Airavaara, for disclosing “GDNF” NM_199231.2) and Dirkx et al. "Targeting of the 67-kDa Isoform of Glutamic Acid Decarboxylase to Intracellular Organelles Is Mediated by Its Interaction with the NH2-terminal Region of the 65-kDa Isoform of Glutamic Acid Decarboxylase." Journal of Biological Chemistry 270.5 (1995): 2241-2246 (hereinafter Dirkx, for disclosing “GAD65” NM_000818.2). This rejection is maintained for the same reasons of record as outlined in the official action dated 3/18/2025. A reply to applicants’ traversal is found below.
A description of Goins, Tavares and Levicoff can be found above. The collection of cited art does not disclose the specific sequences for IL-10, GDNF and GAD65 as described in elected SEQ ID Nos: 14, 13 and 3, respectively.
Claims 28, 30 and 32: It is noted that SEQ ID Nos: 14, 13 and 3 describe human codon-optimized sequences for known genes IL-10 (NCBI NM-012854), GDNF (NM_199231.2) and GAD65 (NCBI NM_000818.2). All of these sequences were known and reported prior to the effective filing date of the application (see Goodman, Airavaara and Dirkx, respectively). Furthermore, codon-optimization techniques are known in the art and routinely used to increase transgene expression in gene therapy systems. Codon-optimization refers to experimental approaches designed to improve the codon composition of a recombinant gene based on various criteria without altering the amino acid sequence. For instance, Gao describes web-based DNA codon optimization algorithms and PCR-based gene assembly approaches to improve the expression of genes in mammalian cells (Gao, abstract).
It would have been prima facie obvious to one of ordinary skill in the art to use the web-based DNA codon optimization algorithms described by Gao to generate codon-optimized vectors which express two or more genes selected from IL-10, GDNF and GAD65 as described by Goins in order to improve transgene expression in humans as a gene therapy for treating pain. SEQ ID Nos: 14, 13 and 3 describe human codon-optimized sequences for known genes IL-10 (NCBI NM-012854), GDNF (NM_199231.2) and GAD65 (NCBI NM_000818.2). Thus, it would have been a matter of combining known prior art elements to apply the optimization approaches described by Gao to the expression vectors identified by Goins to yield the codon-optimized sequences identified in SEQ ID Nos: 14, 13 and 3 with predictable results. One would be motivated to make this combination in order to improve codon composition and expression in human cells. One would have a reasonable expectation of success given that SEQ ID Nos: 14, 13 and 3 correspond to known genes and there exist predictable methods for human codon-optimization. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claimed invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing that neither Tavares, Gao, Goodman, Airavaara nor Dirkx remedy the deficiencies of Goins and Levicoff.
This argument has been fully considered, but was not found persuasive since it would have been prima facie obvious to one of ordinary skill in the art to use the web-based DNA codon optimization algorithms described by Gao to generate codon-optimized vectors which express two or more genes selected from IL-10, GDNF and GAD65 as described by Goins in order to improve transgene expression in humans as a gene therapy for treating pain. SEQ ID Nos: 14, 13 and 3 describe human codon-optimized sequences for known genes IL-10 (NCBI NM-012854), GDNF (NM_199231.2) and GAD65 (NCBI NM_000818.2).
Maintained Nonstatutory Double Patenting Rejections
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 Langi, 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 706.02(1)(1) - 706.02(1)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 15, 17, 26, 28, 30 and 33 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of US Patent No. 11,433,145 in view of Goins et al. "Gene therapy for the treatment of chronic peripheral nervous system pain." Neurobiology of disease 48.2 (2012): 255-270 (hereinafter Goins, reference of record) and Levicoff et al. "Safety assessment of intradiscal gene therapy II: effect of dosing and vector choice." Spine 33.14 (2008): 1509-1516 (hereinafter Levicoff, reference of record). Although the claims at issue are not identical, they are not patentably distinct from each other because the patented claims would anticipate the instant claims if they were available as prior art. This rejection is maintained for the same reasons of record as outlined in the official action dated 3/18/2025. A reply to applicants’ traversal is found below.
Claim 15: The patented claims are drawn to a method for relieving pain in a subject comprising administering a composition comprising a first vector encoding a GAD gene and a second vector encoding an IL-10 gene (Claims 1-3). The patented claims describe administering the compositions directly into the central nervous system of a subject to relieve pain. Furthermore, claim 6 from the patented claims describes a gene encoding GAD consisting of the nucleotide sequence of SEQ ID NO: 3, which is 100% identical to the GAD65 gene described in claim 7 of the instant claims (sequence search results shown below).
Claims 17: The patented claims describe the use of a vector selected from AAV, lentivirus and retrovirus to treat nociceptive pain (claims 1 and 3).
Claim 33: The patented claims describe the use of a physiological carrier which is suitable for injection (Claims 9 and 10).
Claims 26, 28, 30: Claim 6 from the patented claims describes a gene encoding GAD consisting of the nucleotide sequence of SEQ ID NO: 3, which is 100% identical to the GAD65 gene described in claim 7 of the instant claims (sequence search results shown below). The patented claims also disclose sequences for IL-10 (claims 7-8).
PNG
media_image1.png
624
581
media_image1.png
Greyscale
The patented claims do not describe the inclusion of GDNF, however Goins describes gene therapy approaches for the treatment of chronic peripheral nervous system pain (Goins, abstract). Goins describes viral based vectors and approaches for delivering neurotrophin genes (GDNF), neurotransmitter genes (GAD65) and immune modulatory genes (IL-10) for pain treatment. Goins states that the delivery of neurotrophin genes such as GDNF was found to be beneficial for the treatment of chronic pain by lowering levels of cytokine synthesis along with promoting growth (Goins, pg 263, section: Neurophrophic/growth factor gene therapy).
Although the patented claims describe administering the compositions directly into the central nervous system of a subject to relieve pain, they do not describe epidural injection. However, Levicoff provides a clinical, biochemical and histological analysis of AAV vectors encoding various anabolic cytokines and marker genes which are administered via epidural injection into New Zealand white rabbis (Levicoff, abstract). Levicoff shows that “properly dosed and directed gene therapy via epidural injection is both safe and potentially efficacious” (Levicoff, Abstract-conclusion). Levicoff shows that epidural injection resulted in only a mild inflammatory response (Levicoff, Results – Histology).
It would have been prima facie obvious to one of ordinary skill in the art to include GDNF into the different vector formulations to generate GAD, IL-10 and GDNF as single or multiple vectors for the treatment of chronic pain. It is prima facie obvious to combine two compositions, each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose, see MPEP 2144.06. The idea of combining GAD, IL-10 and GDNF into a single vector or combinations thereof flows logically from there having been individually taught in the prior art. Thus, it would have been a matter of combining known prior art elements for one of ordinary skill to arrive at the gene and vector combinations. One would be motivated to make this combination since GAD, IL-10 and GDNF are all known to be useful in managing chronic pain as shown by Goins. One would have a reasonable expectation of success given that the incorporation of multiple transgenes in a single vector is considered routine in the art and there exist predictable methods for constructing such gene expression constructs.
Furthermore, it would have been prima facie obvious to one of ordinary skill in the art to administer the therapeutic AAV vector via epidural injection as described by Levicoff. It would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to use epidural injection, which is a specific form of direct administration into the CNS. One would be motivated to make this combination since Levicoff shows that epidural injection results in only a mild inflammatory response. One would have a reasonable expectation of success given that epidural injection is a species within the genus of CNS delivery methods. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 15, 17, 26 and 33 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the instant rejection by arguing that Goins fails to disclose or suggest an epidural injection which is distinct from an I.T. injection. Applicant argues that Levicoff reports the unsuccessful expression of transgenes via epidural injection. Therefore, the instant claims are not obvious in light of US Patent No. 11,433,145.
This argument has been fully considered, but was not found persuasive since a closer reading of the text concludes with Levicoff’s finding that “properly dosed and directed gene therapy via epidural injection is both safe and potentially efficacious” (Levicoff, Abstract-conclusion). Figure 7 shows that there is no transgene expression across the blood-brain barrier contrary to applicants’ arguments. Furthermore, Goins describes administration routes via intrathecal injection into the spinal cord, which is very closely related to epidural injections (Table 2, cited as “i.t. spinal cord”). Thus, it would have been a matter of combining prior art elements according to known methods to yield predictable results for one of ordinary skill to use epidural injection, which is a specific form of direct administration into the CNS.
Conclusion
THIS ACTION IS MADE FINAL. 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 ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see https://ppair-my.uspto.gov/pair/PrivatePair. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Alexander Nicol
Patent Examiner
Art Unit 1634
/ALEXANDER W NICOL/Examiner, Art Unit 1634