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 .
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1-2, 18-22, 32, and 50-52; drawn to a method of stimulating a cell) in the reply filed on January 9, 2026, is acknowledged.
Claims 12, 24-27, 34, 38-39, 41-43, 46, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Groups II and III), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. 6.91 MHz as the frequency
In light of the Applicant’s elected species, claim 19 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Rejoinder
The species election requirement for the species of frequency has been reconsidered in view of the prior art. The species election has been withdrawn and claim 19 is rejoined.
DETAILED ACTION
The amended claims filed on January 9, 2026, have been acknowledged. Claims 3-11, 13-17, 23, 28-31, 33, 35-37, 40, 44-45, 47, and 49 were cancelled. Claim 2 was amended. Claims 50-52 are new. In light of the Applicant’s elected species, claims 12, 24-27, 34, 38-39, 41-43, 46, and 48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-2, 18-22, 32, and 50-52 are pending and examined on the merits.
Priority
The applicant claims domestic priority from U.S. provisional application No. 63/053,418, filed on July 17, 2020. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Claims 1-2, 18-22, 32, and 50-52 receive domestic benefit from U.S. provisional application No. 63/053,418, filed on July 17, 2020.
Information Disclosure Statement
The information disclosure statements (IDS) filed on January 13, 2023, January 24, 2024, August 23, 2024, January 23, 2025, and January 9, 2026 have been considered.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 refers to the TRPA1 polypeptide having a sequence of NCBI Reference Sequence: XP_016869435.1 as set forth in SEQ ID NO: 1. However, upon searching the NCBI Reference Sequence: XP_016869435.1, it was found that this reference sequence has been suppressed and removed. Although the reference sequence can still be found, it is identified as an obsolete record and it is not clear whether this record will be maintained in the future. Claim 2 still references SEQ ID NO: 1 which is 100% identical to the NCBI Reference Sequence: XP_016869435.1. Therefore, it is recommended that this language be removed and is, instead, just referred to as having the sequence of SEQ ID NO:1. This does not change the scope of the claim as the reference sequence is not considered to add anything to the claim nor add any relevancy as SEQ ID NO: 1 is the same sequence.
As an additional matter, in claim 2, SEQ ID NO: 1 and SEQ ID NO: 4 are the same sequence. The claims are written in such a way as to suggest that SEQ ID NO: 1 and SEQ ID NO: 4 are different sequences. However, they are 100% identical. Therefore, only one of the sequences should be referenced in the claim, not both.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-2, 32, and 50-52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Oh et al. (Current Biology 29: 3386–3401. 2019; referenced in IDS), as evidenced by NCBI (NM_177781.5).
Regarding claims 1, 32, and 50-52, Oh teaches that they examined whether TRPA1 is activated by LILFU. They performed Ca2+ imaging to measure a LILFU-induced Ca2+ increase via TRPA1, which was heterologously expressed in HEK293T with a vector encoding TRPA1. The functional expression of TRPA1 in HEK293T was confirmed by N-methylmaleimide (NMM), a TRPA1 selective agonist (Figures S3A–S3C). TRPA1-expressing cells were plated onto a cover glass, which was placed on top of a custom-built piezoelectric micromachined ultrasonic transducer (pMUT) array (Figure 1F). As a result, LILFU induced Ca2+ increase in TRPA1-expressing HEK293T was more frequently observed (Figures 1G and 1H) with significantly higher peak amplitude compared to untransfected control (Figure 1I). These results show that LILFU can open TRPA1 to cause intracellular Ca2+ increase (page 3387, column 2, paragraph 1 and Figure 2).
Regarding claim 2, Oh teaches that they transfected the HEK293T cells with a TRPA1 encoding vector encoding the cDNA of the full-length mouse TRPA1 (NM_177781.5) (page e4, paragraph 4). NCBI (NM_177781.5) evidences that the protein encoded by NM_177781.5 (top row) has 79.8% sequence similarity to SEQ ID NOs: 1 and 4 (bottom row) of the instant application, as shown below.
1 MKRGLRRILLPEERKEVQGVVYRGVGEDMDCSKESFKVDIEGDMCRLEDFIKNRRKLSKY 60
||| ||:: | |:|| ||||| | :| : ||| || || |::| | ::|| :
1 MKRSLRKMWRPGEKKEPQGVVYEDVPDDTEDFKESLKVVFEGSAYGLQNFNK-QKKLKRC 59
61 EDENLCPLHHAAAEGQVELMELIINGSSCEVLNIMDGYGNTPLHCAAEKNQVESVKFLLS 120
:| : ||:||||||:|||| | || |||: || ||||||||| ||||:||||||||
60 DDMDTFFLHYAAAEGQIELMEKITRDSSLEVLHEMDDYGNTPLHCAVEKNQIESVKFLLS 119
121 QGANPNLRNRNMMSPLHIAVHGMYNEVIKVLTEHKATNINLEGENGNTALMSTCAKDNSE 180
:|||||||| |||:|||||| || |||:||| ||: ::||||||||||:: | :|||
120 RGANPNLRNFNMMAPLHIAVQGMNNEVMKVLLEHRTIDVNLEGENGNTAVIIACTTNNSE 179
181 ALQILLEKGAKLCKSNKWGDYPVHQAAFSGAKKCMELILAYGEKNGYSRETHINFVNHKK 240
||||||:|||| ||||||| :|:|||||||:|:|||:|| :||::||||: ||||:|: |
180 ALQILLKKGAKPCKSNKWGCFPIHQAAFSGSKECMEIILRFGEEHGYSRQLHINFMNNGK 239
241 ASPLHLAVQSGDLDMIKMCLDNGAHIDMMENAKCMALHFAATQGATDIVKLMISSYTGSS 300
|:|||||||:|||:|||||||||| || :| :| |:|||||||||:|||||||||:||
240 ATPLHLAVQNGDLEMIKMCLDNGAQIDPVEKGRCTAIHFAATQGATEIVKLMISSYSGSV 299
301 DIVNAVDGNQETLLHRASLFDHHDLAEYLISVGADINSTDSEGRSPLILATASASWNIVN 360
|||| || ||:||||||||||:||:|||||||||| |||||||||||||||||||||
300 DIVNTTDGCHETMLHRASLFDHHELADYLISVGADINKIDSEGRSPLILATASASWNIVN 359
361 LLLCKGAKVDIKDHLGRNFLHLTVQQPYGLRNLRPEFMQMQHIKELVMDEDNDGCTPLHY 420
||| |||:|||||: |||||||||||||||:|||||||||| ||||||||||||||||||
360 LLLSKGAQVDIKDNFGRNFLHLTVQQPYGLKNLRPEFMQMQQIKELVMDEDNDGCTPLHY 419
421 ACRQGVPVSVNNLLGFNVSIHSKSKDKKSPLHFAASYGRINTCQRLLQDISDTRLLNEGD 480
||||| | ||||||||||||||||||||||||||||||||||||||||||||||||||||
420 ACRQGGPGSVNNLLGFNVSIHSKSKDKKSPLHFAASYGRINTCQRLLQDISDTRLLNEGD 479
481 LHGMTPLHLAAKNGHDKVVQLLLKKGALFLSDHNGWTALHHASMGGYTQTMKVILDTNLK 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
480 LHGMTPLHLAAKNGHDKVVQLLLKKGALFLSDHNGWTALHHASMGGYTQTMKVILDTNLK 539
541 CTDRLDEEGNTALHFAAREGHAKAVAMLLSYNADILLNKKQASFLHIALHNKRKEVVLTT 600
|||||||:||||||||||||||||||:|||:||||:|||:||||||:||||||||||||
540 CTDRLDEDGNTALHFAAREGHAKAVALLLSHNADIVLNKQQASFLHLALHNKRKEVVLTI 599
601 IRNKRWDECLQVFTHNSPSNRCPIMEMVEYLPECMKVLLDFCMIPSTEDKSCQDYHIEYN 660
||:|||||||::|:|||| |:||| ||:|||||||||||||||: |||||||:||:||||
600 IRSKRWDECLKIFSHNSPGNKCPITEMIEYLPECMKVLLDFCMLHSTEDKSCRDYYIEYN 659
661 FKYLQCPLSMTKKVAPTQDVVYEPLTILNVMVQHNRIELLNHPVCREYLLMKWCAYGFRA 720
|||||||| ||| |||||:||||| || |||:|||||||||||:||||||| ||||||
660 FKYLQCPLEFTKK-TPTQDVIYEPLTALNAMVQNNRIELLNHPVCKEYLLMKWLAYGFRA 718
721 HMMNLGSYCLGLIPMTLLVVKIQPGMAFNSTGIINGTSSTHEERIDTLNSFPIKICMILV 780
||||||||||||||||:||| |:|||||||||||| || | | :|| ||: || |||||
719 HMMNLGSYCLGLIPMTILVVNIKPGMAFNSTGIINETSD-HSEILDTTNSYLIKTCMILV 777
781 FLSSIFGYCKEVIQIFQQKRNYFLDYNNALEWVIYTTSIIFVLPLFLNIPAYMQWQCGAI 840
||||||||||| ||||||||||:| :| |||:|||| ||||||||: |||::|||||||
778 FLSSIFGYCKEAGQIFQQKRNYFMDISNVLEWIIYTTGIIFVLPLFVEIPAHLQWQCGAI 837
841 AIFFYWMNFLLYLQRFENCGIFIVMLEVIFKTLLRSTGVFIFLLLAFGLSFYVLLNFQDA 900
|::|||||||||||||||||||||||||| ||||||| ||||||||||||||:||| ||
838 AVYFYWMNFLLYLQRFENCGIFIVMLEVILKTLLRSTVVFIFLLLAFGLSFYILLNLQDP 897
901 FSTPLLSLIQTFSMMLGDINYRDAFLEPLFRNELAYPVLTFGQLIAFTMFVPIVLMNLLI 960
||:||||:||||||||||||||::|||| |||||:|||:| ||::||:|||||||||||
898 FSSPLLSIIQTFSMMLGDINYRESFLEPYLRNELAHPVLSFAQLVSFTIFVPIVLMNLLI 957
961 GLAVGDIAEVQKHASLKRIAMQVELHTNLEKKLPLWYLRKVDQRSTIVYPNRPRHGRMLR 1020
|||||||||||||||||||||||||||:||||||||:||||||:|||||||:|| | ||
958 GLAVGDIAEVQKHASLKRIAMQVELHTSLEKKLPLWFLRKVDQKSTIVYPNKPRSGGML- 1016
1021 FFHYFLNM---QETRQEVPNIDTCLEMEILKQKYRLKDLTSLLEKQHELIKLIIQKMEII 1077
|| | : | |||:|| | |||||||||||||||| |||||||||||||||||||
1017 -FHIFCFLFCTGEIRQEIPNADKSLEMEILKQKYRLKDLTFLLEKQHELIKLIIQKMEII 1075
1078 SETEDEDNHCSFQDRFKKERLEQMHSKWNFVLNAVKTKTH 1117
|||||:|:|||||||||||::|| :|:|| || ||| |||
1076 SETEDDDSHCSFQDRFKKEQMEQRNSRWNTVLRAVKAKTH 1115
Applicant’s specification discloses that "about" is understood as within a range of normal tolerance in the art and identifies within 10% as an example of the meaning of about (page 18, lines 29-33 of Specification). As such, the claim language “at least about 85% identity” is broadly interpreted to include sequences that are at least 76.5% similar to SEQ ID NO: 1 and 4 as applicant has only defined the term “about”, but not “at least”, or “at least about” and ±10% is identified as a possible example of a definition for about. The about is considered to modify the lower bounds of the at least term and allow for values less than 85%.
Claims 1-2, 18-19, 32, 50, and 52 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by United States Patent Application No. 20200023206 (Konofagou), as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014), NCBI (NM_177781.5), and NCBI (NP_015628.2).
Regarding claims 1, 18-19, 32, 50, and 52, Konofagou teaches a method of exciting or inhibiting neurons in mammals using ultrasound. Applying focused ultrasound to sensory neurons can elicit action potentials within the neurons. For example, focused ultrasound can activate mechanosensitive ion channels within the neurons. The neurons can include Aβ, Aδ, and/or C fibers. The sensory neurons can be ex vivo. The focused ultrasound can have a frequency of about 3.57 MHz (paragraphs 0040-0044 and claims 11-20).
Konofagou does not identify that their cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, Konofagou teaches a method of exciting or inhibiting neurons in mammals using ultrasound. Konofagou teaches that they stimulated C fiber sensory neurons from mice (Example 1). NCBI (NM_177781.5) evidences that mice encode a TRPA1 protein (top row) that has 79.8% sequence similarity to SEQ ID NOs: 1 and 4 (bottom row) of the instant application, as shown previously.
Applicant’s specification discloses that "about" is understood as within a range of normal tolerance in the art and identifies within 10% as an example of the meaning of about (page 18, lines 29-33 of Specification). As such, the claim language “at least about 85% identity” is broadly interpreted to include sequences that are at least 76.5% similar to SEQ ID NO: 1 and 4 as applicant has only defined the term “about”, but not “at least”, or “at least about” and ±10% is identified as a possible example of a definition for about. The about is considered to modify the lower bounds of the at least term and allow for values less than 85%.
Furthermore, although Konofagou does not specifically cite that they stimulated human sensory neurons, Konofagou identifies multiple human cell lines that are encompassed within mammalian cells and can be used with their method and connects their method to stimulation of human tissue (paragraphs 0040-0044 and 0125). Therefore, the method of Konofagou encompasses stimulating human sensory neurons. NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
Claims 1-2, 18-19, 21-22, 32, 50, and 52 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by United States Patent Application No. 20160220672 (Chalasani), as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014) and NCBI (NP_015628.2).
Regarding claims 1, 18-19, 21-22, 50, and 52, Chalasani teaches a method of inducing cation influx in a cell, the method comprising expressing a heterologous TRP-4 polypeptide in a cell, and applying ultrasound to the cell, thereby inducing cation influx in the cell, wherein said cell is a human sensory neuron cell and wherein said cell is in vitro or in vivo. The ultrasound has a frequency of about 0.8 MHz to about 4 MHZ. The ultrasonic wave has a focal zone of about 1 cubic millimeter to about 1 cubic centimeter. The method further comprises contacting the cell with a microbubble prior to applying ultrasound (claims 1-11 and paragraph 0024).
Chalasani does not identify that their cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, Chalasani, as stated supra, teaches that their method can be used to stimulate human sensory neurons (claims 1-11 and paragraph 0024). NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over United States Patent Application No. 20200023206 (Konofagou) as applied to claim 1 above.
As an initial matter, Applicant’s specification discloses that "about" is understood as within a range of normal tolerance in the art. ±20% is a commonly used definition for about.
The teachings of Konofagou are as discussed above. Konofagou teaches that the ultrasound frequency used in their can method can be about 5 MHz (paragraph 0091). Konofagou does not define about. Therefore, as ±20% is a commonly used definition for about, this definition is used for Konofagou, as well. About 5 MHz using the ±20% equates to a range of 4-6 MHz and about 6.91 MHz equates to a range of 5.528-8.292.
MPEP 2144.05(I) states in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range).
Therefore, it would have been obvious that the ultrasound frequency could be about 6.91 MHz as about 4 MHz is close to about 6.91 MHz. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Double Patenting
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 Longi, 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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 18-19, 21-22, 32, 50, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 17-35 of U.S. Patent No. 10806951, as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014) and NCBI (NP_015628.2). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 18-19, 21-22, 32, 50, and 52, ‘951 claims multiple methods of stimulating mammalian sensory neurons in vivo or ex vivo with ultrasound to cause a response (e.g. cation influx, cell activity or function, etc.). ‘951 claims that the ultrasound has a frequency of about 0.8 MHz to about 4 MHz and a focal zone of about 1 cubic millimeter to about 1 cubic centimeter. ‘951 claims contacting the cell with a microbubble prior to applying ultrasound (claims 1-13 and 17-35).
‘951 does not identify that their cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, the specification of ‘951 discloses that by “mammal” is meant any warm-blooded animal including a human (paragraph 25). NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
Claims 1 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 17-35 of U.S. Patent No. 10806951 as applied to claim 1 above.
As stated supra, ‘951 claims that the ultrasound has a frequency of about 0.8 MHz to about 4 MHz.
MPEP 2144.05(I) states a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
Therefore, it would have been obvious that the ultrasound frequency could be about 6.91 MHz as about 4 MHz is close to about 6.91 MHz. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-2, 18, 32, 50, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11857809, as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014) and NCBI (NP_015628.2). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1, 18, 32, 50, and 52, ‘809 claims a method for altering the function or activity of human sensory neurons that innervate a targeted tissue portion of a human subject, the method comprising: applying ultrasound energy to the targeted tissue portion from an ultrasound source, wherein the neurons that innervate the targeted tissue portion are configured to express an exogenous, ultrasound-sensitive transmembrane protein, and modulating the membrane potential of the neurons innervating the targeted tissue portion (claims 1-6). Although ‘809 does not specifically state that the stimulation occurs in vivo, in vitro, or ex vivo, it does state that the method is for altering the function or activity of human sensory neurons that innervate a targeted tissue portion of a human subject. This stimulation of a targeted tissue portion can only occur in vivo, in vitro, or ex vivo.
‘809 does not identify that their cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, the claims of ‘809 discloses that the sensory neuron is human (claims 1-6). NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
Claims 1 and 19-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11857809 as applied to claim 1 above, and further in view of United States Patent Application No. 20160220672 (Chalasani).
Regarding claims 19 and 21-22, the teachings of ‘809 are as discussed above. ‘809 claims that the ultrasound-sensitive transmembrane protein can be a non-mammalian TRP-4.
‘809 is silent regarding the ultrasound frequency, focal zone, and contacting the cell with a microbubble.
However, Chalasani teaches a method of inducing cation influx in a cell, the method comprising expressing a heterologous TRP-4 polypeptide in a cell, and applying ultrasound to the cell, thereby inducing cation influx in the cell, wherein said cell is a human sensory neuron cell and wherein said cell is in vitro or in vivo. The ultrasound has a frequency of about 0.8 MHz to about 4 MHZ. The ultrasonic wave has a focal zone of about 1 cubic millimeter to about 1 cubic centimeter. The method further comprises contacting the cell with a microbubble prior to applying ultrasound (claims 1-11 and paragraph 0024).
Therefore, it would have ben obvious that the method of ‘809 could use an ultrasound frequency of about 0.8 MHz to about 4 MHZ and a focal zone of about 1 cubic millimeter to about 1 cubic centimeter, as Chalasani already teaches that these frequencies and focal zones can be used in a method of altering the function (cation influx) in a sensory neuron expressing heterologous TRP-4. Furthermore, it would have been obvious that the method of ‘809 can be modified to introduce a microbubble as Chalasani already teaches that microbubble can contact a cell as part of a method of altering the function (cation influx) in a sensory neuron expressing heterologous TRP-4 and that microbubbles amplify the mechanical deformation of a sound wave and can act as a contrast agent, providing additional benefits to the method (Example 2 and paragraph 0076).
Regarding claim 20, MPEP 2144.05(I) states a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Therefore, it would have been obvious that the ultrasound frequency could be about 6.91 MHz as about 4 MHz is close to about 6.91 MHz. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Claims 1-2, 18-22, 32, 50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of copending Application No. 18/315,383 (reference application), as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014) and NCBI (NP_015628.2). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘383 claims a method of inducing cation or anion influx or efflux in a cell, the method comprising: expressing in the cell a heterologous, mechanosensory polypeptide selected from the group consisting of DmFLYC1, DmFLYC2, DcFLYC1.1, DcFLYC1.2, and DmOSCA, or a variant thereof; and applying ultrasound to the cell, thereby inducing cation or anion influx or efflux in the cell, wherein the cell is a neuronal cell and wherein the cell is in vitro, ex vivo, or in vivo. ‘383 claims wherein the ultrasound has a frequency of about 0.2 MHz to about 20 MHz and a focal zone of about 1 cubic millimeter to about 1 cubic centimeter. ‘383 claims contacting the cell with a microbubble prior to applying ultrasound (claims 1-14).
‘383 does not identify that their neuronal cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, the claims of ‘383 claims that the polynucleotide is encoded by a polynucleotide sequence codon-optimized for expression in a human cell (claim 6). As such, the neuronal cell can be human. NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-2, 18-21, 32, 50, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/311,075 (reference application) , as evidenced by Zygmunt et al. (B. Nilius and V. Flockerzi (eds.), Mammalian Transient Receptor Potential (TRP) Cation Channels, Handbook of Experimental Pharmacology 222. Chapter: TRPA1: 584-614. 2014) and NCBI (NP_015628.2). Although the claims at issue are not identical, they are not patentably distinct from each other.
‘075 claims a method of inducing cation influx in a cell, the method comprising: expressing in the cell a polypeptide selected from MscS, MscL, MscK, MscL G22S, MscMJLR, MscMJ, MscS-Like 3, MseSfam, or MscS-like and applying ultrasound to the cell, thereby inducing cation influx in the cell, wherein the cell is a sensory neuron and wherein the cell is in vivo. ‘383 claims wherein the ultrasound has a frequency of about 0.2 MHz to about 20 MHz and a focal zone of about 1 cubic millimeter to about 1 cubic centimeter (claims 1-19).
‘075 does not identify that their neuronal cells express TRPA1.
However, Zygmunt evidences that Aδ and C fiber sensory neurons express TRPA1 (abstract).
Regarding claim 2, the claims of ‘383 claims that the polynucleotide is encoded by a polynucleotide sequence codon-optimized for expression in a human cell (claim 4). As such, the sensory neuron cell can be human. NCBI (NP_015628.2) evidences that the wild type reference sequence for human TRPA1 is 100% similar to SEQ ID NOs: 1 and 4 of the instant application. As such, human sensory neurons that express wild type TRPA1 would have this sequence.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 19, and 22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. 18/311,075 (reference application) as applied to claim 1 above, and further in view of United States Patent Application No. 20160220672 (Chalasani).
The teachings of ‘075 are as discussed above.
‘075does not claim contacting the cell with a microbubble.
However, Chalasani teaches a method of inducing cation influx in a cell, the method comprising expressing a heterologous TRP-4 polypeptide in a cell, and applying ultrasound to the cell, thereby inducing cation influx in the cell, wherein said cell is a human sensory neuron cell and wherein said cell is in vitro or in vivo. The ultrasound has a frequency of about 0.8 MHz to about 4 MHZ. The ultrasonic wave has a focal zone of about 1 cubic millimeter to about 1 cubic centimeter. The method further comprises contacting the cell with a microbubble prior to applying ultrasound (claims 1-11 and paragraph 0024).
Therefore, it would have been obvious that the method of ‘075 can be modified to introduce a microbubble as Chalasani already teaches that microbubbles can contact a cell as part of a method of altering the function (cation influx) in a sensory neuron expressing a heterologous mechanosensory polypeptide and that microbubbles amplify the mechanical deformation of a sound wave and can act as a contrast agent, providing additional benefits to the method (Example 2 and paragraph 0076).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631