CTNF 16/379,763 CTNF 82281 1649 Notice of Pre-AIA or AIA Status 07-03-fti AIA 1. The present application is being examined under the pre-AIA first to invent provisions. DETAILED ACTION Continued Examination Under 37 CFR 1.114 07-42-04 AIA 2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3 February 2025 has been entered. Status of Application, Amendments and/or Claims 3. The amendment of 2/3/2025 has been entered in full. Claims 41, 44, 47 and 51 have been amended. Claims 41-45, 47, 49, and 51-52 are currently pending. 4. Claims 41-45, 47, 49, and 51-52, drawn to a method of identifying a modulator of pain, are being considered for examination in the instant application. Rejection withdrawn 5. Upon consideration of appropriate amendment of claims 41, and 44, the rejection under 35 U.S.C. 112, second paragraph is withdrawn. New Objections and Maintained Rejections Claim Rejections - 35 USC § 103 07-20-fti 6. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action: (a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made. 7. NOTE: Upon further reconsideration, the 103 rejection of claims 51-52 over Raymon et al. (1999), Jat (2002), and Keswani et al (2003) has been withdrawn. 07-21-fti 8. Claim s 51-52 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Raymon et al. ( The Jour Neurosc 19: 5420-5428, 1999) (IDS), in view of Pilcher et al ( Soc Neurosc Meeting abstract 27: pp 1525, 2001 (abstract only) (IDS), and in further view of Keswani et al ( Ann Neurol 53: 57-64, 2003), as evidenced by Primary Neurons (What Are Primary Neurons and Why Are They Used? - Biology Insights, downloaded on 5/16/2026, 5 pages). The rejection is maintained and extended to amended claims for reasons of record in the Office Action dated 1 August 2024. Appropriate modifications are made to address the amendments . 9. The claims are directed to a method of identifying a pain modulator comprising immortalizing a primary dorsal root ganglion (DRG) neuronal cell; contacting the immortalized DRG neuronal cell with a candidate modulator; and determining if said modulator binds to or modulates the activity of the immortalized DRG cell, wherein the DRG cell comprises an oncogene and human telomerase reverse transcriptase protein (hTERT), or SV40 large T-antigen and hTERT (claim 51), and the oncogene is selected from those recited in claim 52. 10. Raymon et al teach obtaining human primary DRGs from embryos, and immortalizing the primary DRG neuronal cell (Materials and Methods: para 1, 2). It is well understood in the relevant art that a primary neuron is directly derived from a living tissue, and maintained in a controlled dish environment (like culture), as evidenced by Primary Neurons (What Are Primary Neurons and Why Are They Used? - Biology Insights, downloaded on 5/16/2026, 5 pages; page 1, para 1). Since Raymon et al teach dissecting human DRGs from embryos, the DRGs of the reference are primary DRG neuronal cells. Raymon et al teach that the immortalized human DRG cells (and an immortalized DRG neuronal cell line) comprises v -myc oncogene, wherein the DRG cell differentiates to sensory neurons expressing functional capsaicin receptors characteristic of the nociceptive DRG neurons (Abstract; Results, para 1; para spanning pages 5423-5424). Raymon et al also teach that DRG sensory neurons are nociceptive and activated by painful peripheral stimuli. The reference strongly suggests that the immortalized DRG cell line will be useful for the “identification and validation of new targets for the treatment of pain” (Abstract; page 5420, para 1, 2). 11. Raymon et al do not teach that the immortalized DRG neuron comprises hTERT and SV40 large T-antigen as the oncogene. 12. Pilcher et al. teach the production of immortalized human neural stem cells lines for treatment of neurological conditions. The reference teaches a method comprising, sequentially infecting the cells with retroviral vectors encoding the SV40tsA58/U19 large T antigen (Tag) and human telomerase reverse transcriptase (hTERT) (abstract). The reference also teaches that conditional immortality is conferred by infecting with both Tag and hTERT. The reference further teaches that the expression of hTERT alone “is not sufficient for the immortalization of human neural stem cells” (abstract), thereby indicating that immortalization is attained when the cells comprise both hTERT and Tag . 13. Raymon et al or Pilcher et al do not teach the steps directed to “contacting” and “determining”, as recited in claim 51. 14. Keswani et al teach the development of an in vitro model for screening potential neuroprotective compounds for treating painful sensory toxic neuropathy associated with HIV infection. The reference teaches the use of DRG sensory neurons in culture as the model, wherein the dose dependent toxicity caused by molecules such as ddC, is corrected by the immunophilin ligand FK506 that protects the DRG cell from the toxicity of ddC (i.e., modulates the activity of DRG cell) (Abstract; page 57, cols 1, 2). Keswani et al teach adding (contacting) compounds like ddC and neuroprotective agents like FK506 or cyclosporin A (CSA) to DRG neurons in culture, and measuring the neurite length or apoptosis of DRG neurons (determining modulation of DRG cell activity), thereby identifying neuroprotection by the immunophilin ligands (Materials and Methods, Results; Fig. 2). 15. It would therefore, have been obvious to the person of ordinary skill in the art at the time the claimed invention was made to modify the method of using the immortalized DRG cell with an oncogene that would be useful for drug development for pain as taught by Raymon et al, by also adding hTERT for immortalization of neuronal cells as taught by Pilcher et al, and demonstrating successful drug screening for pain modulators using DRG cells in view of the teachings of Keswani et al. The person of ordinary skill would be motivated to have immortalized cells having both hTERT and oncogene or Tag, as Pilcher et al teach that the expression of Tag along with hTERT is essential for conditional immortality of the cell. The person of ordinary skill in the art would have been motivated to use immortalized DRG cells for drug screening as such cells can readily expand and differentiate so as to provide “a renewable and homogeneous source of sensory neurons”, and thereby "facilitate the identification and validation of new targets for the treatment of pain”, thus adding an advantage over primary DRG cultures, which have fewer neurons and “are not easily transfectable with exogenous genes” (Raymon et al: page 5420, para spanning cols 1, 2; page 5427, col 1, last para). The person of ordinary skill in the art would have expected success because generating immortalized cell lines and screening of pharmaceutical compounds using the same, was a subject of research at the time the invention was made. 16. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art. 07-21-fti 17. Claim s 41-45, 47 and 49 are rejected under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Keswani et al (2003) in view of Raymon et al. (1999), and in further view of Pilcher et al (2001), as evidenced by Primary Neurons (2026). The rejection is maintained and extended to amended claims for reasons of record in the Office Action dated 1 August 2024. Appropriate modifications are made to address the amendments . 18. The claims are directed to a method of identifying a pain modulator comprising contacting sensory neurons differentiated from an immortalized DRG neuronal cell with a candidate modulator, wherein the DRG is immortalized from primary DRG cells, and determining if said modulator binds to and/or modulates the sensory neurons, wherein: the DRG cell comprises an oncogene and human telomerase reverse transcriptase protein (hTERT), or SV40 large T-antigen and hTERT (claims 41, 44, 47), and the oncogene is selected from those recited in claims 45 and 49. The claims also recite that the DRG cell expresses nociceptive markers (claim 42), and other markers as in claim 43. 19. The teachings of Keswani et al are set forth above. 20. Even though Keswani et al teach using DRG sensory neurons for screening neuroprotective compounds for treating painful sensory neuropathy, Keswani et al do not explicitly teach that the sensory neurons are differentiated from an immortalized DRG neuron. 21. The teachings of Raymon et al are set forth above. Raymon et al teach that the DRG cell differentiates to sensory neurons expressing functional capsaicin receptors characteristic of the nociceptive DRG neurons (Abstract; Results, para 1; para spanning pages 5423-5424). The reference also teaches that DRG sensory neurons are activated by painful peripheral stimuli. Please note that the limitations in claims 42, 43 following the term "wherein" or “where”, are known properties of the DRG neurons, therefore, would be inherent to the neuron, absent any evidence to the contrary. The limitations are not part of the claimed method, rather recite a property of the claimed DRG neurons. For example, TRPV1 is a well-known capsaicin receptor that was known to be present in the DRG neuron at the time of filing of the instant invention. Raymon et al also teach that the properties of the immortalized DRG cell line indicate that “sensory neuronal precursor cells exist in the human embryonic DRG” (Discussion, para 1). The reference teaches that the HD10.6 DRG clonal cell line is a human sensory neuronal line, which will be valuable for “basic research, as well as for the discovery of novel drug targets and clinical candidates” (Abstract), clearly suggesting that sensory neurons derived from DRG cells upon differentiation, can be used in screening assays. 22. Raymon et al do not teach that the immortalized DRG neuron also comprises hTERT and SV40 large T-antigen as the oncogene. 23. The teachings of Pilcher et al are set forth above. 24. It would therefore, have been obvious to the person of ordinary skill in the art at the time the claimed invention was made to modify the method of successful drug screening for pain modulators using DRG sensory neuronal cells in view of the teachings of Keswani et al, wherein the sensory neurons can be differentiated from an immortalized DRG cell with an oncogene as taught by Raymon et al, by also adding hTERT for immortalization as taught by Pilcher et al. The person of ordinary skill would be motivated to have immortalized cells having both hTERT and oncogene or Tag, as Pilcher et al teach that the expression of Tag along with hTERT is essential for conditional immortality of the cell. The person of ordinary skill in the art would have been motivated to use sensory neurons differentiated from DRG cells, as the immortalized DRG clonal cell line is a human sensory neuronal line. which can readily expand and differentiate so as to provide “a renewable and homogeneous source of sensory neurons”, and thereby "facilitate the identification and validation of new targets for the treatment of pain”, thus adding an advantage over primary DRG cultures, which have fewer neurons and “are not easily transfectable with exogenous genes” (Raymon et al: page 5420, para spanning cols 1, 2; page 5427, col 1, last para). The person of ordinary skill in the art would have expected success because screening of pharmaceutical compounds using immortalized cell lines and cells differentiated from the same, was a subject of research at the time the invention was made. 25. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art. Applicant’s Remarks 26. Traversing the 103 rejections, Applicant argues that Raymon uses embryonic DRG stem cells to produce an immortalized cell line. Applicant also argues that Jat teaches the requirement of conditionally inducible oncogene in a method of producing cells “which retain immortality prior to transplantation, but which lose immortality on transplantation”. Applicant adds that Jat’s “neural cells” are neuroepithelial cells which are different from DRG cells. Applicant further argues that Keswani et al teach the use of non-immortalized DRG cells. 27. Applicant asserts that in contrast to the reference teachings, the present invention is directed to generation of “neuronal cell lines with nociceptive properties from primary DRG cells and not from embryonic tissues”. Applicant emphasizes that till date “attempts to immortalize neuronal cell lines have achieved little success”, and that using a temperature sensitive mutant T antigen for immortalization of neurons has produced low efficiency. In conclusion, Applicant alleges that the cited combination of Raymon, Jat and Keswani fails to obviate the instantly claimed method, and emphasizes that the amendment of claim 51 now recites immortalizing a primary DRG cell. Applicant therefore, requests withdrawal of the rejection. 28. Applicant argues that the teachings of the combination of Raymon, Pilcher and Keswani, requiring either an embryonic DRG cell (Raymon), or a non-immortalized DRG cell (Keswani), coupled with a conditionally inducible oncogene of Pilcher et al, also fail to obviate the instantly claimed invention. Applicant therefore, requests withdrawal of the rejection. 29. With respect to the combination of Keswani, Raymon and Pilcher, Applicant points to the amendment of claims 41 and 47, which recite that “DRG is immortalized from primary DRG cells”. Applicant therefore, requests reconsideration and withdrawal of the rejection. 30. Applicant’s arguments with regards to the Raymon, Jat and Keswani combination is considered. As stated above, upon reconsideration of the claims and analysis of Applicant’s comments, the Jat reference and the rejection using the reference is withdrawn. The arguments against Jat teachings are therefore, moot. 31. Applicant’s argument that Keswani uses a non-immortalized DRG neuron is considered but not found to be persuasive. As noted in the rejection, Raymon et al strongly suggest that immortalized DRG cells can be useful for the identification and validation of new targets for pain treatment, thereby implicitly indicating the use of immortalized DRG cells in the method as claimed. Keswani teachings were only used for showing that DRG cells can be used for identifying pain modulators or compounds for treating pain, comprising contacting DRG neurons with the compound. 32. Applicant’s argument that the present invention is directed to using primary DRG cells for generation of neuronal cell lines, which is in contrast to using cells from embryonic tissues, is considered but not found to be persuasive. As stated in the rejection, Raymon et al teach obtaining human primary DRG cells from embryos, and immortalizing the primary DRG neuronal cell , which differentiates to sensory neurons expressing functional nociceptive receptors. It is repeated that a primary neuron is derived from a living tissue, and maintained in a dish environment (like culture). The cited art therefore, teaches immortalization of DRG neurons from primary DRG cells, thereby meeting the claimed requirement. 33. Applicant’s argument that the inventive method comprises cells that are “not from embryonic tissues”, and are not coupled with a conditionally-inducible oncogene, is considered, however, are not found to be persuasive, because arguments that rely on particular distinguishing features are not persuasive when those features are not recited in the claims. In the present situation, there is no requirement for obtaining the DRG cell from a particular tissue, since the claims either recite using an immortalized DRG cell (claim 51), or recite using sensory neurons differentiated from an immortalized DRG cell (claims 41, 47), as the starting step. Likewise, the claims generically recite the use of an oncogene or a SV40 large T-antigen (which can include any oncogene suitable for immortalization). It is noted that the claims must be interpreted as broadly as their terms reasonably allow. See Ex parte Oetiker , 23 USPQ2d 1641 (BPAI, 1992). Applicant is reminded that the claims define the subject matter of his invention, and that the specification (Applicant’s invention) cannot be relied upon to read limitations into the claims. 34. Applicant seems to argue each reference on an individual basis. Applicant is however, reminded that one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc. , 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). 35. Applicant’s repeated emphasis that till date immortalization of neuronal cell lines have achieved little success, is apparently indicating an unexpected or surprising feature of the inventive method. This is however, not found to be persuasive as the combination of the above references proves that the knowledge and expertise for the claimed method of immortalizing a primary DRG neuronal cell line and identifying a pain modulator using the immortalized DRG neuronal cell was known in the art and the results were expected to be successful. The prima facie obviousness of the claimed invention in view of the combined references, therefore, provides sufficient reasoning, and nullifies Applicant’s allegations of the improper teachings in the individual references. Applicant’s assertion of unexpected results does not overcome the rejection because of obvious expected properties taught in the prior art, either explicitly or implicitly. “Where the unexpected properties of a claimed invention are not shown to have a significance equal to or greater than the expected properties, the evidence of unexpected properties may not be sufficient to rebut the evidence of obviousness”. In re Nolan , 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977). 36. For the above stated reasoning, Raymon and the remaining references therefore, properly render the instantly claimed invention obvious. The rejections as stated above are therefore, maintained. New Claim Objections 07-29-01 AIA 37. Claim s 47 and 51 are objected to because of the following informalities: 38. In claim 47, line 2, the article “a” is missing before “cell”. 39. Line 2 of claim 51 should have a semicolon (;) after “cell” . Appropriate correction is required. Conclusion 40. No claims are allowed. 41. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm. 42. 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. 43. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. 44. 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. /A. D./ Examiner, Art Unit 1675 15 May 2026 /KIMBERLY BALLARD/Primary Examiner, Art Unit 1675 Application/Control Number: 16/379,763 Page 2 Art Unit: 1675 Application/Control Number: 16/379,763 Page 3 Art Unit: 1675 Application/Control Number: 16/379,763 Page 4 Art Unit: 1675 Application/Control Number: 16/379,763 Page 5 Art Unit: 1675 Application/Control Number: 16/379,763 Page 6 Art Unit: 1675 Application/Control Number: 16/379,763 Page 7 Art Unit: 1675 Application/Control Number: 16/379,763 Page 8 Art Unit: 1675 Application/Control Number: 16/379,763 Page 9 Art Unit: 1675 Application/Control Number: 16/379,763 Page 10 Art Unit: 1675 Application/Control Number: 16/379,763 Page 11 Art Unit: 1675 Application/Control Number: 16/379,763 Page 12 Art Unit: 1675 Application/Control Number: 16/379,763 Page 13 Art Unit: 1675
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