Notice of Pre-AIA or AIA Status
1. 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 and/or Claims
2. The response dated 8/29/2025 is acknowledged and entered into record. Claims 1-20 are currently pending.
3. Applicant’s election without traverse of the Neurokinin species (b) Neurokinin B; and the conditional receptor and agonist combination species a) hM3DREADD and clozapine-N-oxide, in the reply filed on 29 August 2025 is acknowledged.
4. Claims 1-20, drawn to a kit and a vector comprising a first and a second nucleic acid, are under consideration in the instant application.
Claim Objection
5. Claim 19 is objected to because of the following informalities:
Claim 19 has a typographical error as it begins with “the vector…” (emphasis added). The “t” of “the” should be capitalized. Appropriate correction is required.
Claim Rejections - 35 USC § 112-Second paragraph
6. 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.
7. 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.
8. Claims 17 and 19 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
9. The word “neurokinin” in claim 17 is rejected as being indefinite. There is insufficient antecedent basis for this limitation in the claim as there is no recitation of “neurokinin" in claim 15 or claim 12 (from which claim 15 is depending). Please note that this issue could be overcome by amending claim 17 to depend from claim 16. Appropriate correction is required.
For consideration of prior art, claim 17 will be construed as depending from claim 16.
10. Claim 19 is rejected for depending from “claim 19” – i.e. claim 19 is depending from itself. Since many claims recite “neuropeptidergic neuron” (e.g. claims 2, 3, 9, 14, 15, 18), it is not apprehensible as to which claim would be the one that claim 19 would depend from. For the stated confusion, claim 19 will not be considered for prior art search until further clarification/correction.
Claim Rejections - 35 USC § 103
11. 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.
12. Claims 1, 3, 5-10, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (Neuron 83: 444-454, 2014).
13. The claims are directed to a kit comprising a first nucleic acid encoding a neuropeptide, and a second nucleic acid encoding a conditional receptor configured to increase the activity of a neuron upon binding of an agonist, wherein each of the nucleic acids are operably linked to a promoter configured to drive expression in a neuron in two different vectors (claims 1(b), 3) and both promoters are neuropeptide promoters (claim 7); wherein: the neuropeptide is neurokinin or neurokinin B (claims 5, 6); the kit further comprises the agonist or stimulus (claim 8); and the neuron is a neuropeptidergic neuron (claim 9) of one or more types listed in claim 10.
14. Andero et al teach that the centromedial amygdala (a subdivision of CeA or central amygdala) is the brain region for fear expression and that Tac2 gene (in rodents) encoding neurokinin B or NkB is expressed in neurons of this region (neuropeptidergic neurons), and is required for the modulation of fear memory (Abstract; Figures 3A, B). The reference teaches a viral vector comprising the Tac2 gene (lentvirus-Tac2) operably linked to Ubc promoter resulting in overexpression of Tac2 in amygdala neurons (i.e. configured to drive expression in a neuropeptidergic neuron) (Figure 5B, 5E; page 448, col 1). The reference also teaches another vector comprising DREADD (conditional receptor) using the hM4Di-mCherry AAV virus operably linked to a human synapsin (promoter) (second vector) (Figure 6A; page 452, Production of Recombinant viral vectors; Surgery and Injection of virus) resulting in expression of the receptor in the Tac2 cells within the CeA, but not in any other region of the brain (configured to drive expression in a neuropeptidergic neuron) (para spanning pages 448 and 449). The reference further teaches the use of CNO, wherein CNO binds to DREADD (page 449, col 1, para 1) (instant claims 1, 3, 5-6, 8-10). With reference to instant claim 7, it is noted that para 0045 of the instant specification teaches that a neuropeptide promoter specifically drives expression in a neuropeptide neuron. Since both promoters taught by Andero et al result in expression in the amygdala or CeA neurons (neuropeptidergic neuron), the promoters are obviously expected to be neuropeptide promoters, absent any evidence to the contrary.
15. Andero et al do not teach the term “kit” comprising the claimed elements (vectors, promoters, nucleic acids, agonist), even though the reference teaches all said elements (vector constructs and CNO) and their use in experiments described in the reference. It is well understood that a kit is merely a package having the claimed components and instruction for use. Because Andero et al teach all the claimed components, the only difference between the prior art product and a claimed product is the instruction for use. Since the printed matter is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). Where the printed matter is not functionally related to the composition, the printed matter will not distinguish the invention from the prior art in terms of patentability. In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983).
16. Andero et al do not teach a kit comprising both, nucleic acid constructs and the agonist (CNO). The reference however, teaches the use of the vectors and CNO within a study for understanding the role of Tac2 gene (para spanning pages 448, 449). In the absence of unexpected results, it would have been prima facie obvious to one of ordinary skill in the art to combine all components as taught in the prior art into a single kit or package as each of the components are used in complementary experiments for understanding the role of Tac2 gene. The instant situation is amenable to the type of analysis set forth in In re Kerkhoven,205 USPQ 1069 (CCPA 1980) wherein the court held 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 for a third composition that is to be used for the very same purpose since the idea of combining them flows logically from their having been individually taught in the prior art. Applying the same logic to the instant product claims, given the teaching of the prior art of the claimed vectors and agonist for use in understanding the role of Tac2 gene, it would have been obvious to have one kit comprising both vectors and agonist, because the idea of doing so would have logically followed from their having been individually taught in the prior art to be useful for the same purpose. One of ordinary skill in the art would have reasonably expected to use a single kit having all components, as all elements were known and used in the prior art for understanding the role of Tac2 gene.
17. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
18. Claims 1, 3-10, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (2014) in view of Dissen et al (Reprod Domest Anim 52: 354-358 (1-9), April 2017), and as evidenced by Neurokinin B – Wikipedia, pages 1-6, downloaded from en.wikipedia.org/wiki/Neurokinin_B, on 2/15/2020.
19. Claim 4 recites that the first and second vectors are AAV.
20. The teachings of Andero et al are set forth above.
21. Andero et al teach AAV comprising DREADD (conditional receptor) gene. Andero et al however, do not teach that Tac2 (first nucleic acid) is in AAV vector.
22. Dissen et al teach Tac3 nucleic acid (encoding neurokinin B) in AAV vector and its administration to neurons of the hypothalamus of the cat, wherein Tac3 is expressed in the hypothalamus, and is essential in reproduction (Abstract; Introduction, para 2). It is noted that NkB is encoded by Tac3 in humans, and Tac2 in rodents (see Neurokinin B – Wikipedia; para 2). Dissen et al also teach that AAV or recombinant AAVs are safe vectors, exhibit diverse tropism, can be genetically modified “to alter their biological properties” for appropriate clinical use, can transduce the central nervous system and can cross the blood brain barrier (page 3, para 2).
23. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the NkB gene in a lentvirus vector as taught by Andero et al, by considering AAV vector comprising NkB gene in view of the teachings of Dissen et al. The person of ordinary skill would have been motivated as AAVs are safe vectors, exhibit diverse tropism, can be genetically modified “to alter their biological properties” for appropriate clinical use, can transduce the central nervous system cells, and can cross the blood brain barrier (Dissen et al), therefore, is more effective for neuronal expression of peptides. The person of ordinary skill would have expected success because AAVs were well known, and efficient delivery and expression of neuropeptides using AAVs in the CNS was an ongoing effort, before the effective filing date of the instant invention.
24. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
25. Claims 1, 3-10, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (2014) in view of Shen et al (Hum Gen Ther 11: 1509-1519, 2000).
26. The teachings of Andero et al are set forth above.
27. Andero et al teach AAV comprising DREADD (conditional receptor) gene. Andero et al however, do not teach that Tac2 (first nucleic acid) is in AAV vector.
28. Shen et al teach gene therapy for Parkinson’s disease (PD) for the production of dopamine in the striatum by the expression of two or three different enzymes involved in the biosynthetic pathway of dopamine. The reference teaches three different enzyme genes – tyrosine hydroxylase (TH), aromatic-L-amino acid decarboxylase (AADC) and GTP cyclohydrolase I (GCH) , each in separate AAV vectors under the control of human cytomegalovirus or CMV promoter, wherein the administration of the genes resulted in triple transduction, which enhanced dopamine production and persistently improved rotational behavior in PD rats, as compared to rats administered with TH alone (Abstract; page 1151, Plasmids; In vivo transduction; Figure 2; page 1517, col 2, para 2).
29. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the vector comprising NkB gene in lentvirus vector and DREADD gene in AAV vector as taught by Andero et al, by considering AAV vectors for all genes view of the teachings of Shen et al. The person of ordinary skill would have been motivated as adeno-associated virus or AAV are attractive vector candidates as these lack any disease associated with wild type virus, along with an absence of immune response, and showing of long-term transgene expression “that renders it more clinically practical” in neuroscience applications and gene therapy (Shen et al. page 1510, Introduction, para 1). The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
30. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
31. Claims 1 and 3-11, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (2014) in view of Shen et al (2000) and in further view of Roth BL (Neuron 89: 683-694 (1-25), 2/2016).
32. Claim 11 recites that the conditional receptor is hM3DREADD, and the agonist is clozapine-N-oxide.
33. The teachings of Andero et al and Shen et al are set forth above.
34. Andero et al or Shen et al do not teach that the conditional receptor is hM3DREADD.
35. Roth teaches Designer Receptors Exclusively Activated by Designer Drugs (DREADD) and their use in chemogenetic methods for identifying neuronal circuitry, cell signaling and behavior in subjects, and understanding brain function (Abstract). The reference teaches that hM3DqDREADD (hM3DREADD) is typically used for enhancing neuronal firing in neurons (activation of neurons), and that hM3DqDREADD can be activated by clozapine-N-oxide or CNO. Roth teaches that other DREADD molecules like hM4Di can also be activated by CNO (page 7, para 1, 3). The reference concludes that DREADDs in combination with CNO modulate “electrophysiology and behavior” in subjects, and is a crucial step in basic and translational neuroscience research (page 10). The reference also teaches hM3DqDREADD expression in specific cells like neurons using promoters and AAV (page 6, para 3).
36. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify a nucleic acid encoding NkB and that encoding hM4Di DREADD in AAV vectors in view of Andero et al, and Shen et al, by considering hM3DREADD in AAV based upon the teachings of Roth. The person of ordinary skill would have been motivated to consider hM3 DREADD as it enhances neuronal firing and activates Gq signaling in neurons (Roth). The person of ordinary skill would be motivated to also consider hM3 DREADD for studying the effect of neuronal activation on neurokinin expression in neurons. The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references.
37. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
38. Claims 1-11, 12-14, 16-18 and 20, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (2014), Shen et al (2000)/Dissen et al (April 2017) and Roth BL (2/2016), in view of Foti et al (Gene Ther 16: 1314-1319 (1-13), 2009).
39. The claims recite a single vector with one or two promoters (claims 1(a), 2, 12). The claims also recite a vector comprising a first nucleic encoding a neuropeptide, and a second nucleic acid encoding a conditional receptor, wherein each of the nucleic acids are operably linked to the single promoter configured to drive expression in a neuropeptidergic neuron (claims 12, 14); wherein the vector is an adeno-associated virus (AAV) (claim 13); the neuropeptide is neurokinin or neurokinin B (claims 16, 17); the neuron is a neuropeptidergic neuron (claim 18); the conditional receptor comprises hM3DREADD and the agonist is clozapine-N-oxide (claim 20).
40. The teachings of Andero et al, Shen et al, Dissen et al and Roth are set forth above.
41. Andero et al Shen et al, Dissen et al or Roth do not teach that the first and second nucleic acid are administered in a single vector AAV.
42. Foti et al teach a proteolytic approach for the “expression and secretion of multiple gene products from a single AAV vector”. The reference teaches a recombinant AAV vector having two genes (green fluorescence protein or GFP and galanin) under the control of one promoter, which upon infusion into the piriform cortex, results in the expression of both GFP and galanin in neurons (Abstract; page 3, para 2, 3; page 4, para 5). The reference also teaches that consideration of more than one gene from a single virus vector enhances the benefit of gene therapy from “increasing the absolute number of gene products per virus vector to the delivery of distinct genes”, thereby resulting in better coordination of the “delivery of multiple therapeutic genes” facilitating effective treatment (Introduction, para 1; page 4, para 4).
43. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the vectors comprising nucleic acids encoding a neuropeptide neurokinin and DREADD in different AAV vectors in view of the combined teachings of Andero et al Shen et al, Dissen et al and Roth, to having both genes in a single AAV vector in view of the teachings of Foti et al. The person of ordinary skill would have been motivated as different genes in a single vector would ensure that the transduced cell expresses both genes; and further the presence of a single promoter would allow one transcript, hence preventing differential promoter silencing, transcriptional interference and unequal levels of gene expression” thus leading to effective delivery of different genes to neurons (Foti et al, page 2, para 1). The person of ordinary skill would have expected success because development of vector constructs with one or more genes and single or dual promoters for research and clinical applications was an actively ongoing effort, before the effective filing date of the instant invention.
44. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
45. Claims 1, 12 and 15, are rejected under AIA 35 U.S.C. 103 as being unpatentable over Andero et al (2014) in view of Gascon et al (J Neurosci Meth 168: 104-112, 2008).
46. The claims also recite a single vector with two nucleic acids and two promoters (claims 1(a)(ii), 12), wherein each nucleic acid is operably linked to a promoter configured to drive expression specifically in neuropeptidergic neurons (claim 15).
47. The teachings of Andero et al are set forth above.
48. Andero et al do not teach two promoters in a single vector.
49. Gascon et al teach neuron specific and regulated expression by single lentviral vectors, which provide valuable tools for neuronal function studies (Abstract). The reference teaches the development of a dual promoter viral vector comprising two human synapsin (hSYN) promoters for driving the expression of two cDNAs of two reporter fluorescent proteins (DsRed and EGFP) in a neuron-specific manner (page 105, col 1, para 2; Fig, 1A; Materials and methods, para 1; Results, 3.1). The results show co-expression of the cDNAs in neurites and cell bodies of cultured neurons, which is mediated by a single dual promoter vector (Results – 3.3, page 109; Fig. 3). Teaching the advantages of dual promoter viral vectors, the reference states that the presence of all molecular components in one unique vector “guarantees expression of the two cDNAs in the target cells”, hence could prove “an important tool for the understanding of neuronal function in normal and pathological conditions” (para spanning pages 111 and 112).
50. It would have been, therefore, obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the vectors comprising nucleic acids encoding a neuropeptide neurokinin and DREADD, each operably linked to a different promoter in different vectors as taught by Andero et al, by having a single vector with two different promoters for driving the expression of two nucleic acids in view of Gascon et al. The person of ordinary skill would have been motivated having two promoters in a single vector as the presence of all molecular components in one unique vector “guarantees expression of the two cDNAs in the target cells”, hence could prove “an important tool for the understanding of neuronal function in normal and pathological conditions” (Gascon et al). The person of ordinary skill would have expected success because development of vector constructs with one or more genes and single or dual promoters for research and clinical applications was an actively ongoing effort, before the effective filing date of the instant invention.
51. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Conclusion
52. No claims are allowed.
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/A. D./
Examiner, Art Unit 1675
3 February 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675