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 .
DETAILED ACTION
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
2. Applicant’s amendment filed June 23, 2026 is acknowledged. Claims 2-5 and 8-9 are cancelled. Claims 1 and 6 are amended. Claims 1, 6-7 and 10-13 are pending in this application. Claims 11-13 are withdrawn without traverse (filed 08/22/2024) from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 22, 2024.
3. Claims 1, 6-7 and 10 are under examination with respect to SEQ ID NO:2 in this office action.
4. Applicant’s arguments filed on June 23, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
5. The rejection of claims 4-5 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 is moot because the claims are canceled.
The rejection of claims 4-5 under 35 U.S.C. 103 as being unpatentable over Qi et al. (WO2017/123559; issued as US9856497) in view of Mujica et al. (US20190159436) is moot because the claims are canceled.
Claim Rejections/Objections Maintained
In view of the amendment filed on June 23, 2026, the following rejections are maintained.
Claim Rejections - 35 USC § 112
6. 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.
Claims 1, 6-7 and 10 stand 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. The rejection is maintained of record and the reasons set forth below.
Claims 1, 6-7 and 10 as amended encompass a genus of nucleic acid constructs encoding a genus of fusion polypeptides comprising an intracellular domain of Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14, wherein Trk is a high-affinity receptor for a neurotrophic factor selected from the group consisting of TrkA, TrkB and TrkC; and a membrane localization sequence, wherein the membrane localization sequence is a farnesylation sequence or a myristoylation sequence; wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase; wherein the nucleic acid construct is a vector.
Briefly, the limitation “having an amino acid sequence selected from group of SEQ ID NO:2, 6, 9, 12 and 14” include fragments within SEQ ID NOs: 2, 6, 9, 12 or 14.
Applicant has not disclosed sufficient species for the broad genus of nucleic acid construct encoding the broad genus of fusion polypeptide including an intracellular domain of Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14, wherein Trk is TrkA, TrkB or TrkC; and a membrane localization sequence that is a farnesylation sequence or a myristoylation sequence wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase; wherein the nucleic acid construct is a vector.
The specification fails to teach the detailed structures and sequences and characteristics for the claimed genus of nucleic acid construct encoding the claimed genus of fusion polypeptide which comprises an intracellular domain of Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14, wherein Trk is a high-affinity receptor for a neurotrophic factor selected from the group consisting of TrkA, TrkB and TrkC; and a membrane localization sequence, wherein the membrane localization sequence is a farnesylation sequence or a myristoylation sequence; wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase; wherein the nucleic acid construct is a vector.
Response to Arguments
On p. 5-6 of the response, Applicant argues that: i) the rejection has been overcome in view of amendment to claim 1 by reciting “an intracellular domain of Trk consisting of an amino acid sequence selected from group consisting of SEQ ID NO:2, 6, 9, 12 and 14” and cites para. [0063]0[0064], [0066]; CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4, para. [0113]; CA-TrkA/AAV-CA-TrkA (SEQ ID NOs:6 and 8), para. [0144]; and CA-TrkC/AAV-CA-TrkC (SEQ ID NO:9 and 11), para [0145], Examples 1and 5 and Figures 4 and 9 in support of the arguments. ii) the specification provides support for the specific fernesylation and myristoylation sequences and cites para. [0068]-[0069]; [0142], Fig.8 and para.[0068] in support for the argumetns. iii) the specification provides support for the claimed nucleic acid construct which is limited to a vector and cites para. [0072]-[0076] and AAV-CA-TrkB in example 1 and AAV-CA-TrkA and AAV-CA-TrkC in Example 5 in support of arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.01-2163.03, the specification fails to provide sufficient description or information or evidence to demonstrate that Applicant is in possession of the claimed genus of nucleic acid construct encoding a genus of fusion polypeptide comprising an intracellular domain of Trk consisting of an amino acid sequence selected from SEQ ID NOs: 2, 6, 9, 12 and 14 and a membrane localization sequence that is a fernesylation sequence or a myristoylation sequence, and wherein the fusion polypeptide does not include an extracellular domain of any type of tyrosine kinase inhibitor because:
i. There is no well-established structural and functional relationship or correlation between the claimed genus of nucleic acid construct and the nucleic acid construct of CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4), iSH-TrkB (SEQ ID NO: 5), CA-TrkA/AAV-CA-TrkA (SEQ ID NO: 8) or CA-TrkC/AAV-CA-TrkC (SEQ ID NO:11) shown paragraphs [0111]-[0152], Examples 1-6.
The limitation “an intracellular domain of Trk consisting of an amino acid sequence selected from group of SEQ ID NO:2, 6, 9, 12 and 14” include fragments within SEQ ID NO: 2, 6, 9, 12 or 14 because the limitation “an amino acid sequence of SEQ ID NO:2, 6, 9, 12 or 14” includes fragments within the sequence of SEQ ID NO:2, 6, 9, 12 or 14. There is no structural and functional relationship between the fragment within SEQ ID NO: 2, 6, 9, 12 or 14 and the intracellular domain of SEQ ID NO:2, 6, 9, 12 or 14.
The limitation “a membrane localization sequence that is a farnesylation sequence or a myristoylation sequence” is not limited to the sequences shown in para. [0069], SEQ ID NO:1, or [0113], [0144]-[0145]; or [0142], Fig.8 of the published application but also encompass structurally and functionally undefined sequences. The specification provides no well-established structural and functional relationship between the claimed genus of farnesylation sequence or the claimed genus of myristoylation sequence as a membrane localization sequence and the specific sequences shown in para. [0113] or SEQ ID NO:1 shown in para. [0113] of the published specification. The specification fails to teach what other specific sequences and structures are required by the claimed genus of farnesylation sequence or the claimed genus of myristoylation sequence.
It is also not known what the structure of the claimed genus of extracellular domain of any type of RTK is, and what sequences are excluded by the claimed fusion polypeptide. There is no well-established structural and functional relationship or correlation between the claimed genus of extracellular domain of any type of RTK and the sequences that are excluded by the claimed fusion polypeptide. There is no well-established structural and functional relationship or correlation between the claimed genus of extracellular domain of any type of RTK and the sequences that are excluded by the claimed fusion polypeptide and the nucleic acid construct of CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4), iSH-TrkB (SEQ ID NO: 5), CA-TrkA/AAV-CA-TrkA (SEQ ID NO: 8) or CA-TrkC/AAV-CA-TrkC (SEQ ID NO:11) shown paragraphs [0111]-[0152], Examples 1-6.
ii. The specification fails to teach the detailed structures and sequences and characteristics for the claimed genus of nucleic acid construct encoding the claimed genus of fusion polypeptide comprising a genus of intracellular domain of Trk consisting of an amino acid sequence selected from SEQ ID NO: 2, 6, 9, 12 or 14 including fragments within SEQ ID NO:2, 6, 9, 12 or 14, and a genus of farnesylation sequence or myristoylation sequence as a membrane localization sequence, and wherein the fusion polypeptide does not include a genus of extracellular domain of a genus of any type of receptor tyrosine kinase (RTK).
There is no well-established structural and functional relationship or correlation between the claimed genus of nucleic acid construct and the nucleic acid construct of CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4), iSH-TrkB (SEQ ID NO: 5), CA-TrkA/AAV-CA-TrkA (SEQ ID NO: 8) or CA-TrkC/AAV-CA-TrkC (SEQ ID NO:11) shown paragraphs [0111]-[0152], Examples 1-6.
There is no information regarding the relation of the structure of other structurally and functionally undefined intracellular domains of Trk including fragments within recited SEQ ID NO: to the function of SEQ ID NO:2 (the intracellular domain of TrkB in CA-TrkB/AAV-CA-TrkB), SEQ ID NO:6 (the intracellular domain of TrkA in CA-TrkA/AAV-CA-TrkA) or SEQ ID NO:9 (the intracellular domain of TrkC in CA-TrkC/AAV-CA-TrkC).
There is also no information regarding the relation of structure of other structurally and functionally undefined farnesylation sequences or myristoylation sequences as a membrane localization sequence to localize a protein at a membrane.
There is no well-established structural and functional relationship or correlation between the claimed genus of fusion polypeptide that does not include an extracellular domain of any type of tyrosine kinase inhibitor and the fusion protein encoded by CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4), iSH-TrkB (SEQ ID NO: 5), CA-TrkA/AAV-CA-TrkA (SEQ ID NO: 8) or CA-TrkC/AAV-CA-TrkC (SEQ ID NO:11).
The specification fails to teach what other structures/amino acid sequences can or cannot be included/changed in the claimed fusion polypeptide, the claimed intracellular domain of Trk and the claimed membrane localization sequence. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of nucleic acid construct, the claimed genus of fusion polypeptide, the claimed genus of intracellular domain of Trk and the claimed genus of membrane localization sequence that induces lipid modification of an amino acid in order to preserve the activity of CA-TrkB/AAV-CA-TrkB (SEQ ID NO:4), iSH-TrkB (SEQ ID NO: 5), CA-TrkA/AAV-CA-TrkA (SEQ ID NO: 8) or CA-TrkC/AAV-CA-TrkC (SEQ ID NO:11).
Since the common characteristics/features of other nucleic acid constructs, other fusion polypeptides, other intracellular domains of Trk including fragments within recited SEQ ID NOs: and other membrane localization sequences are unknown, a skilled artisan cannot envision the functional correlations of the claimed genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of nucleic acid constructs, fusion polypeptides, intracellular domains of Trk and membrane localization sequences inducing lipid modification of an amino acid.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
Therefore, the claimed nucleic acid construct, the claimed pharmaceutical composition and the claimed neural cells transfected with the claimed nucleic acid constructs have not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Accordingly, the rejection of claims 1, 6-7 and 10 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 is maintained.
Claim Rejections - 35 USC § 112
7. Claims 1, 6-7 and 10 stand 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 due to new matter. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection. The rejection is maintained of record and the reasons set forth below.
Briefly, the specification provides no support for the new limitations “Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14…and a membrane localization sequence…...wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase (RTK)….” recited in instant claim 1 because the new limitations were not clearly disclosed in the specification and claims as originally filed, and now change the scope of the instant disclosure as filed.
The specification only discloses “the fusion polypeptide does not include the extracellular domain of Trk and/or the transmembrane domain. In a more preferable example, the fusion polypeptide includes neither the extracellular domain of Trk nor the transmembrane domain” (see para. [0061]; [0112] of the published Application).
The specification only discloses “the intracellular domain of Trk refers to (i) a polypeptide corresponding to an intracellular domain of a high-affinity receptor (Trk) for a neurotrophic factor, which high-affinity receptor is a single-span transmembrane protein, and (ii) a polypeptide functionally equivalent to this polypeptide. The intracellular domain is also referred to as a cytoplasmic domain” (see para. [0063] of the published application) or “The intracellular domain of Trk is only required to (1) have tyrosine kinase activity and/or (2) be capable of activating an intracellular signaling pathway downstream of Trk in a case where the intracellular domain is localized at a cell membrane….the activation in the form of an increased expression of at least one selected from Ras, ERK1/2, PI3K, Akt, phospholipase C-γ, and the like” (see para. [0065]), “…….A polypeptide having an amino acid sequence represented by any oen of SEQ ID NO:2, 6, 9, 12, or 14…..” (see para. [0066] of the published application).
Accordingly, in the absence of sufficient recitations for “a nucleic acid construct encoding a fusion polypeptide including an intracellular domain of Trk consisting of an amino acid…..wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase (RTK)…”, the specification does not provide adequate written description to support the new limitations recited in claim 1. Support is not found for the new limitations as disclosed in the original specification and thus the recitations constitute new matter absent evidence for their support.
Response to Arguments
On p. 7-8 of the response, Applicant argues that the specification provides support for the limitation “does not include an extracellular domain of any type of receptor tyrosine kinas (RTK)” because the specification states “does not include the extracellular domain of Trk….” and teaches CA-TrkB which does not an extracellular domain of TrkB; and cites para. [0061]; [0112] in support of the arguments.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2163, MPEP §§2163.06 and MPEP § 608.01(o), the claimed nucleic acid construct recited in instant claim 1 was not disclosed in the specification and claims originally filed and is new matter for the following:
i. As acknowledged by Applicant, the specification only discloses “the fusion polypeptide does not include the extracellular domain of Trk and/or the transmembrane domain. In a more preferable example, the fusion polypeptide includes neither the extracellular domain of Trk nor the transmembrane domain” (see para. [0061]; [0112] of the published Application). The para. [0061]; [0112] only disclose “does not include ‘the extracellular domain of Trk’, not an extracellular domain of “any type of receptor tyrosine kinase (RTK)”.
ii. As also acknowledged by Applicant, the specification only discloses “the intracellular domain of Trk refers to (i) a polypeptide corresponding to an intracellular domain of a high-affinity receptor (Trk) for a neurotrophic factor, which high-affinity receptor is a single-span transmembrane protein, and (ii) a polypeptide functionally equivalent to this polypeptide. The intracellular domain is also referred to as a cytoplasmic domain” (see para. [0063] of the published application) or “The intracellular domain of Trk is only required to (1) have tyrosine kinase activity and/or (2) be capable of activating an intracellular signaling pathway downstream of Trk in a case where the intracellular domain is localized at a cell membrane….the activation in the form of an increased expression of at least one selected from Ras, ERK1/2, PI3K, Akt, phospholipase C-γ, and the like” (see para. [0065]), “…….A polypeptide having an amino acid sequence represented by any one of SEQ ID NO:2, 6, 9, 12, or 14…..” (see para. [0066] of the published application). The para. [0063] and [0065] does not disclose “an intracellular domain of Trk consisting of an amino acid sequence of SEQ ID NO:2, 6, 9,12 or 14” recited in instant claim1.
The specification provides no support for the new limitations “Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14…and a membrane localization sequence…...wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase (RTK)….” recited in instant claim 1. Thus, the specification does not provide adequate written description to support the new limitations recited in claim 1. Support is not found for the new limitations as disclosed in the original specification and thus the recitations constitute new matter absent evidence for their support.
Accordingly, the rejection of claims 1, 6-7 and 10 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 due to new matter is maintained.
Claim Rejections - 35 USC § 103
8. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 6-7 and 10 stand rejected under 35 U.S.C. 103 as being unpatentable over Qi et al. (WO2017/123559; issued as US9856497) in view of Mujica et al. (US20190159436). The rejection is maintained of record and the reasons set forth below.
Claims 1, 6-7 and 10 as amended are drawn to a nucleic acid construct encoding a fusion polypeptide including an intracellular domain of Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14, wherein Trk is a high-affinity receptor for a neurotrophic factor selected from the group consisting of TrkA, TrkB and TrkC; and a membrane localization sequence, wherein the membrane localization sequence is a farnesylation sequence or a myristoylation sequence; wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase; wherein the nucleic acid construct is a vector.
Briefly, Qi (WO2017/123559) teaches a nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide), a pharmaceutical composition comprising the claimed nucleic acid construct (as in claim 7; see paragraphs [00382]-[00383]; [00390]-[00393]) and a neural cell transfected with the nucleic acid construct in an expressible manner (as in claim 10; see paragraphs [00257]; [00262]; [00102]-[00107]); wherein the chimeric receptor polypeptide includes an intracellular domain of a Trk receptor and a membrane localization sequence/membrane targeting sequence comprising a membrane targeting peptide and directing a polypeptide to a plasma membrane or membrane of a cellular organelle (see paragraphs [00409]-[00412]; [00100]-[00107]); and wherein the membrane localization sequence includes a farnesylation sequence: CAAX motif recited in claim 1 (see paragraphs [00211]-[00213]); and wherein the nucleic acid construct is a vector including an adeno-associated virus vector as recited in claims 1 and 6 (see paragraphs [00106]; [00362]-[00364]).
While Qi does not explicitly teach that the intracellular domain of Trk consisting of an amino acid sequence of instant SEQ ID NO: 2 (elected) recited in claim 1, Mujica (US20190159436) teaches that the intracellular domain of TrkB consisting of the amino acid sequence of SEQ ID NO:62, which is 100% identical to the/an amino acid sequence of instant SEQ ID NO: 2 (elected) (see the sequence alignment below; para. [0115]; [0207]; [0232]). person of ordinary skill in the art would have recognized that selecting and applying the known sequence of instant SEQ ID NO:2 as the intracellular domain of TrkB and the known technique disclosed by Mujica to the Qi’s nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) would have yielded the predictable result of the claimed nucleic acid construct/vector encoding a chimeric receptor polypeptide/fusion polypeptide comprising an intracellular domain of Trk consisting of an/the amino acid sequence of instant SEQ ID NO:2 and a membrane localization sequence/membrane targeting sequence including a farnesylation sequence: CAAX motif as recited in claim 1, and resulted in an improved product because the intracellular domain of TrkB consisting the known sequence of SEQ ID NO:2 has been used in a nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) for targeting and regulating specific gene expression in specific intracellular compartments for therapeutic and pharmaceutical purposes. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known sequence of SEQ ID NO:2 as the intracellular domain of TrkB and the known technique disclosed by Mujica to the Qi’s nucleic acid construct/vector encoding a chimeric receptor polypeptide (i.e. fusion polypeptide), and yield the predictable result of the claimed nucleic construct encoding a fusion polypeptide including an intracellular domain of Trk consisting of an/the amino acid sequence of instant SEQ ID NO:2 and a membrane localization sequence that is a farnesylation sequence: CAAX motif recited in claim 1.
Response to Arguments
On p. 8-11 of the response, Applicant argues that: i) the claimed construct is constitutively membrane-anchor Trk intracellular domain that signals through the receptor’s own intracellular tyrosine-kinase pathway without extracellular ligand-binding domain; ii) the combination of Qi with Mujica fails to establish a prima facie case because: 1. Qi uses the receptor’s intracellular region as a carrier for separate actuator released upon a binding event which is different mode of operation from the claimed construct in which the Trk intracellular domain itself drives the receptor’s downstream signaling pathway; 2. Qi does not teach the claimed nucleic acid construct because the chimeric receptor polypeptide disclosed by Qi comprises at least an intracellular domain of RTK and requires binding to the antigen/ligand; 3. Mujica teaches a full-length, ligand-dependent receptor and provides no motivation to isolate intracellular domain, omit the extracellular domain thereby create a constitutively active, ligand-independent signaling construct; 4. There is no articulate reason or predictable substitution.
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. Note that the claimed fusion polypeptide encoded by the claimed nucleic acid construct recited in amended claim 1 comprises: 1) an intracellular domain of Trk consisting of an amino acid sequence selected from the group consisting of SEQ NOs: 2, 6, 9, 12 and 14 including any fragments within recited SEQ ID NOs:; 2) a farnesylation sequence or a myristoylation sequence as a membrane localization sequence; 3) the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase; 4) wherein the nucleic acid construct is a vector.
The claimed fusion protein recited in amended claim 1 does not exclude an extracellular domain or antigen binding from the extracellular domain of receptors with non-receptor tyrosine kinase (non-RTK).
The chimeric receptor polypeptide (i.e. fusion polypeptide) encoded by a nucleic acid construct disclosed by Qi includes 1) an intracellular domain of a receptor including Trk and 2) a membrane localization sequence/membrane targeting sequence including a farnesylation sequence: CAAX motif recited in claim 1 (see paragraphs [00211]-[00213]) for a membrane targeting and directing a polypeptide to a plasma membrane or membrane of a cellular organelle (see paragraphs [00409]-[00412]; [00100]-[00107]), and 3) does not include an extracellular domain of Trk, regardless whether the chimeric receptor polypeptide of Qi requires binding to a ligand/antigen.
ii. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., “constitutively signaling Trk construct”, “an isolated Trk intracellular domain to the membrane by a lipid-modification sequence so that the domain signals constitutively through its own kinase activity” are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
iii. In this case, Qi teaches a nucleic acid construct/vector encoding a chimeric receptor polypeptide (i.e. fusion polypeptide), wherein the chimeric receptor polypeptide includes an intracellular domain of Trk and a farnesylation sequence: CAAX motif as a membrane localization sequence/membrane targeting sequence for membrane targeting peptide and directing a polypeptide to a plasma membrane or membrane of a cellular organelle (see paragraphs [00211]-[00213]; [00409]-[00412]; [00100]-[00107]). Qi teaches a vector including an adeno-associated virus vector in claims 1 and 6 (see paragraphs [00106]; [00362]-[00364]); a pharmaceutical composition comprising the claimed nucleic acid construct as in claim 7 (see paragraphs [00260]; [00416] [00382]-[00383]; [00390]-[00393]); and a neural cell transfected with the claimed nucleic acid construct in an expressible manner as in claim 10 (see paragraphs [00257]; [00262]; [00102]-[00107]).
While Qi does not teach that the intracellular domain of Trk consisting an/the amino acid sequence of SEQ ID NO: 2 (elected) in claim 1, Mujica teaches that the intracellular domain of TrkB consisting of the amino acid sequence of SEQ ID NO:62, which is 100% identical to the amino acid sequence of instant SEQ ID NO:2 (see the sequence alignment; p. 22, table 1; Example 1, paragraph [0207]).
A person of ordinary skill in the art would have recognized that selecting and applying the known sequence of SEQ ID NO:2 as the intracellular domain of TrkB and the known technique disclosed by Mujica to the Qi’s nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) would have yielded the predictable result of the claimed nucleic acid construct encoding a chimeric receptor polypeptide/fusion polypeptide comprising an intracellular domain of Trk consisting of an/the amino acid sequence of instant SEQ ID NO:2 and a membrane localization sequence/membrane targeting sequence including a farnesylation sequence: CAAX motif, and resulted in an improved product.
Using the known sequence of SEQ ID NO:2 as the intracellular domain of TrkB in Q’s nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) would inherently constitutively signal through the intracellular domain of TrkB, and expand application of the Qi’s nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) in targeting and regulating specific gene expression in specific intracellular compartments for therapeutic and pharmaceutical purposes, and would increase patient’s satisfaction with treatment of gene therapy using a nucleic acid construct encoding a chimeric receptor polypeptide (i.e. fusion polypeptide) in targeting and regulating specific gene expression in specific intracellular compartments.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known sequence of SEQ ID NO:2 as the intracellular domain of TrkB and the known technique disclosed by Mujica to the Qi’s nucleic acid construct/vector encoding a chimeric receptor polypeptide (i.e. fusion polypeptide), and yield the predictable result of the claimed nucleic construct encoding a fusion polypeptide including an intracellular domain of Trk consisting of an/the amino acid sequence of instant SEQ ID NO:2 and a membrane localization sequence including a farnesylation sequence: CAAX motif, and wherein the fusion polypeptide does not include an extracellular domain of any type of receptor tyrosine kinase.
Accordingly, the rejection of claims 1, 6-7 and 10 under 35 U.S.C. 103 as being unpatentable over Qi et al. (WO2017/123559; issued as US9856497) in view of Mujica et al. (US20190159436) is maintained.
Conclusion
9. NO CLAIM IS ALLOWED.
10. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Mujica (US20190159436) under the 103 rejection teaches that the intracellular domain of TrkB consisting of the amino acid sequence of instant SEQ ID NO:2 (see the sequence alignment below).
SEQ ID NO:2
BGJ78559
(NOTE: this sequence has 2 duplicates in the database searched.
See complete list at the end of this report)
ID BGJ78559 standard; protein; 384 AA.
XX
AC BGJ78559;
XX
DT 11-JUL-2019 (first entry)
XX
DE Homo sapiens TRKB/NTRK2 cytoplasmic domain, SEQ 62.
XX
KW NTRK2 protein; TRKB protein; TrkB receptor; animal disease model;
KW protein kinetics; tropomyosin receptor kinase B.
XX
OS Homo sapiens.
XX
CC PN US2019159436-A1.
XX
CC PD 30-MAY-2019.
XX
CC PF 30-NOV-2018; 2018US-00206330.
XX
PR 30-NOV-2017; 2017US-0592905P.
PR 23-APR-2018; 2018US-0661373P.
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CC PA (REGN ) REGENERON PHARM INC.
XX
CC PI Mujica AO, Tang Y, Lee JD, Gao M, Croll S, Macdonald L, Hu Y;
CC PI Romano C;
XX
DR WPI; 2019-46625M/44.
DR N-PSDB; BGJ78571.
DR SWISSPROT; Q16620.
DR REFSEQ; NP_006171.
XX
CC PT New non-human animal useful for assessing activity of human-TRKB-
CC PT targeting reagent in vivo, comprises genetically modified endogenous
CC PT tropomyosin receptor kinase B (TrkB) locus encoding TRKB protein.
XX
CC PS Example 1; SEQ ID NO 62; 118pp; English.
XX
CC The present invention relates to a novel non-human animal useful for
CC assessing the activity of human-tropomyosin receptor kinase B
CC (TRKB/Ntrk2)-targeting reagent (antibody) in vivo. The non-human animal
CC comprises a genetically modified endogenous TrkB locus encoding a TRKB
CC protein, wherein the TRKB protein comprises a cytoplasmic domain, a
CC transmembrane domain, and an extracellular domain, and all or part of the
CC extracellular domain is encoded by a segment of the endogenous TrkB locus
CC that has been deleted and replaced with an orthologous human TRKB
CC sequence. The invention further provides: a method for assessing the
CC activity of the human-TRKB-targeting reagent; a method for producing the
CC non-human animal; a cell derived from the non-human animal; and a method
CC for targeting a vector for generating the genetically modified endogenous
CC TrkB locus encoding the TRKB protein.
XX
SQ Sequence 384 AA;
Query Match 100.0%; Score 2051; Length 384;
Best Local Similarity 100.0%;
Matches 384; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 KLARHSKFGMKDFSWFGFGKVKSRQGVGPASVISNDDDSASPLHHISNGSNTPSSSEGGP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 KLARHSKFGMKDFSWFGFGKVKSRQGVGPASVISNDDDSASPLHHISNGSNTPSSSEGGP 60
Qy 61 DAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFLAECY 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DAVIIGMTKIPVIENPQYFGITNSQLKPDTFVQHIKRHNIVLKRELGEGAFGKVFLAECY 120
Qy 121 NLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFYGVCVEGDPLIMVFE 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 NLCPEQDKILVAVKTLKDASDNARKDFHREAELLTNLQHEHIVKFYGVCVEGDPLIMVFE 180
Qy 181 YMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQIAAGMVYLASQHFVHRDLA 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 YMKHGDLNKFLRAHGPDAVLMAEGNPPTELTQSQMLHIAQQIAAGMVYLASQHFVHRDLA 240
Qy 241 TRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWMPPESIMYRKFTTESDVWS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 TRNCLVGENLLVKIGDFGMSRDVYSTDYYRVGGHTMLPIRWMPPESIMYRKFTTESDVWS 300
Qy 301 LGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRK 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 LGVVLWEIFTYGKQPWYQLSNNEVIECITQGRVLQRPRTCPQEVYELMLGCWQREPHMRK 360
Qy 361 NIKGIHTLLQNLAKASPVYLDILG 384
||||||||||||||||||||||||
Db 361 NIKGIHTLLQNLAKASPVYLDILG 384
11. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
September 22, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
