DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendments
Applicant's amendments filed 8/17/2026 to claims 1, 6, 8, 13, 15, 18, 22, 25, 26, and 37 have been entered. Claims 2-5, 7, 9-12, 14, 16, 17, 19, 20, 24, 27-30, 32-34, 44, 46, and 48-50 are canceled. Claims 1, 6, 8, 13, 15, 18, 21-23, 25, 26, 31, 35-43, 45, 47, and 51-53 remain pending, of which claims 1, 6, 8, 13, 15, 18, 21-23, 25, 26, 31 and 35-37 are being considered on their merits. Claims 38-43, 45, 47, and 51-53 remain withdrawn from consideration. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.
Claim Rejections - 35 USC § 112
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.
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.
Claims 1, 6, 8, 13, 15, 18, 21-23, 25, 26, 31, and 35-37 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “about” in claims 1, 6, 8, 13, 21-23, 26, 35, and 36 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Correction is required.
In so much that claims 15, 18, 25, 31, and 37 depend from claim 1 and do not resolve the point of confusion, these claims must be rejected with claim 1 as indefinite.
Claim Rejections - 35 USC § 103
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.
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.
Claims 1, 6, 8, 13, 15, 18, 21-23, 25, 26, 31, and 35-37 are rejected under 35 U.S.C. 103 as being unpatentable over Lai (WO 2018/113723) in view of Deisseroth et al. (US 2015/0144490), and as evidenced by Otanicar (of record) and Tatham (of record).
Regarding the cyclic borate ester of claim 1, the claim is read in light of the specification that combining N-methylglucamine and boric acid inherently yields the claimed cyclic borate ester. See page 17 of the disclosure. Therefore, any combination of N-methylglucamine and boric acid taught by the prior art is reasonably presumed to inherently generate/yield the cyclic borate ester of claim 1 absent any showing to the contrary. See M.P.E.P. § 2112(V) and 2112.01(I); when the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established, and the USPTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).
Lai’s general disclosure relates to a composition and a method for clearing tissue for subsequent three-dimensional analysis (see Abstract). Regarding claim 1, Lai discloses a clearing composition comprising: a homogenizing agent, a cytoplasmic, water-soluble refractive index adjusting agent, and a membrane, lipid-soluble RI adjusting agent, wherein the lipid-soluble RI adjusting can include triethanolamine-borate acid and tissue clearing kit may further comprise sodium borate (p13, lines 6-13; p19, lines 26-30), and excipients/diluents lacking hydrochloric acid. Therefore, Lai discloses the composition of claim 1.
Regarding claim 1, Lai discloses the homogenizing agent can be selected from N-methylglucamine, urea, and ethylenediamine (p12, lines 6-20).
Regarding claims 1 and 6, Lai teaches that the composition may comprise 5-60% homogenizing agent and 5-70% lipid-soluble adjusting agent, wherein the lipid-soluble agent may be a triethanolamine-borate agent (p13, lines 6-13; p14, line 22; p16, line 16). An ordinary artisan would recognize that the homogenizing agent and borate compound have a molar ratio between about 0.5 to about 2 or about 1 given the percentage ranges above.
Further, it is noted that where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (See MPEP 2144.05 I). It is noted that “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation” (See MPEP 2144.05 II).
Regarding claims 8 and 26, Lai teaches an exemplary buffer comprising 0.2 M sodium borate (p5, lines 11-18).
Regarding claims 1, 21, and 22, Lai discloses that the water-soluble RI adjusting agent can be selected from iohexol, sodium thiosulfate, and polyethylene glycol (p12, line 33 through p13, line 5), lipid-soluble RI adjusting agent can be 2,2’-thiodiethanol, polyethylene glycol, glycerol, ethylene glycol, sodium dodecyl sulphate, trimethylamine, triethanolamine, triethanolamine-borate acid adduct (p13, lines 6-13). Lai discloses a composition comprising boric acid or sodium borate/disodium tetraborate (see col. 9, lines 40-44; col. 14, line 1).
Regarding claim 23, Lai teaches a compositing comprising 20% N-methylglucamine, 25% 2,2’-thiodiethanol, and 32% iohexol (see Table 3). Given the teachings above regarding claim 1, an ordinary artisan including boric acid in the composition would recognize that the molar ratio of N-methylglucamine to boric acid between about 0.5 to 2 could be achieved by routine experimentation and optimization.
Regarding claim 25, Lai teaches tissue clearing compositions free of detergents (see the paragraph spanning pages 7-8).
Regarding claim 26, Lai teaches comprising 20% N-methylglucamine, 35% propylene glycol, and 32% iohexol (see Table 3). Given the teachings above regarding claim 1, an ordinary artisan including boric acid in the composition would recognize that the molar ratio of N-methylglucamine to boric acid between about 0.5 to 2 could be achieved by routine experimentation and optimization.
Regarding claim 29, Lai teaches comprising 10% urea, 25% 2,2’-thiodiethanol, and 32% iohexol (see Table 3). Given the teachings above regarding claim 1, an ordinary artisan including boric acid in the composition would recognize that the molar ratio of N-methylglucamine to boric acid between about 0.5 to 2 could be achieved by routine experimentation and optimization.
Regarding claim 31, Lai discloses the composition can further comprise excipients, such as solvents, dispersion media, diluents, other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like (p13, lines 23-32).
Regarding claim 36, Lai teaches the composition an additional diluent including buffers with pH 6.8-7.6, 7.4, or 8.5 (p19, lines 26-30).
Regarding claims 13, 15, 18, and 35, Lai teaches iohexol as a water-soluble adjusting agent and propylene glycol as a lipid-soluble and water-miscible adjusting agent (see claim 6). As evidenced by Otanicar, propylene glycol has a refractive index of 1.4399 (see page 1). As evidenced by Tatham, iohexol has a refractive index of 1.46 (see page 1, col. 2, para. 2). The refractive index of the water-soluble adjusting agent is within 10% of the refractive index of the lipid-soluble adjusting agent. An ordinary artisan would recognize that the RI adjusting agents are added to composition to form a composition with an RI value closer to the RI value of the agents; therefore, the refractive index of the composition would be adjusted to be around 1.4-1.5 given the RI values of the agents. It is noted that where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (See MPEP 2144.05 I).
Regarding claim 37, when the prior art product seems to be identical except that the prior art is silent as to an inherent function, property, or characteristic, a rejection under 35 U.S.C 103 can be made (See MPEP 2112 III). Given Lai teaches a tissue clearing composition comprising a borate compound, then it would inherently possess the characteristic of showing improved tissue clearing capacity as recited in claim 37.
Regarding claim 1, Lai does not teach boric acid (i.e. CAS number 10043-35-3). Regarding claims 1 and 26, Lai does not teach any N-methylglucamine-to-boric-acid. Regarding claims 8 and 26, Lai does not teach a boric acid concentration of 6.335% w/v.
Deisseroth teaches methods and compositions for preparing a biological specimen for microscopic analysis (Abstract). Deisseroth teaches boric acid and sodium borate as an exemplary buffer in compositions for tissue clearing (¶0054), reading on claim 1. Deisseroth teaches adding boric acid to a final concentration of 200 mM in a tissue clearing composition ([0124]), reading in-part on claims 8 and 26.
Regarding the boric acid of claim 1, a person of ordinary skill in the art would have had a reasonable expectation of success in substituting the boric acid of Deisseroth for the sodium borate of Lai because boric acid and sodium borate are both explicitly taught as being useful for THE SAME PURPOSE as buffers in tissue clearing compositions. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Regarding the molar ratio of N-methylglucamine and boric acid of claims 1 and 26 and the boric acid concentration claims 8 and 26, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Deisseroth clearly teaches that 200 mM boric acid is effective as a buffer in tissue clearing compositions and Lai teaches the combination of N-methylglucamine with the conjugate salt of borate. Thus, the burden is shifted back to establish criticality of the claimed molar ratio of N-methylglucamine and boric acid and boric acid concentration by objective evidence.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
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, 6, 8, 13, 15, 18, 21-23, 25, 26, 31, and 35-37 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1, 3-6, 9, 18, and 20-22 of U.S. Patent No. 11,130,931 in view of Deisseroth et al. (US 2015/0144490).
Regarding the cyclic borate ester of claim 1, the claim is read in light of the specification that combining N-methylglucamine and boric acid inherently yields the claimed cyclic borate ester. See page 17 of the disclosure. Therefore, any combination of N-methylglucamine and boric acid taught by the prior art is reasonably presumed to inherently generate/yield the cyclic borate ester of claim 1 absent any showing to the contrary. See M.P.E.P. § 2112(V) and 2112.01(I); when the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established, and the USPTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of the claimed product. Whether the rejection is based on ‘inherency’ under 35 U.S.C. 102, on ‘prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977).
Although the claims are not identical, they are not patentably distinct from each other because:
Regarding claims 1 and 21-26, the ‘931 patent discloses a tissue clearing composition, comprising 10-50% w/v each of N-methylglucamine, iohexol, and 2,2′-thiodiethanol (see claims 1, 20, and 21 of the ‘931 patent), and buffers lacking hydrochloric acid (claim 22 of the ‘931 patent).
Regarding claim 1, the ‘931 patent does not claim boric acid (i.e. CAS number 10043-35-3). Regarding claims 1 and 26, the ‘931 patent does not claim any N-methylglucamine-to-boric-acid. Regarding claims 8 and 26, the ‘931 patent does not claim a boric acid concentration of 6.335% w/v.
Deisseroth teaches methods and compositions for preparing a biological specimen for microscopic analysis (Abstract). Deisseroth teaches boric acid and sodium borate as an exemplary buffer in compositions for tissue clearing (¶0054), reading on claim 1. Deisseroth teaches adding boric acid to a final concentration of 200 mM in a tissue clearing composition ([0124]), reading in-part on claims 8 and 26.
It would have been obvious to one of ordinary skill in the art to add to or modify the composition of the ‘931 patent to include the boric acid taught by Deisseroth. A person of ordinary skill in the art would have had a reasonable expectation of success to do so because both the ‘931 patent and Deisseroth are directed towards tissue clearing compositions. The ordinary artisan would have been motivated to do so because Deisseroth teaches that boric acid as an exemplary buffer in compositions for tissue clearing, and so the addition of boric acid to the composition of the ‘931 patent would be predictably advantageous as a compatible buffer.
Regarding the molar ratio of N-methylglucamine and boric acid of claims 1 and 26 and the boric acid concentration claims 8 and 26, optimization within prior art conditions or through routine experimentation will generally not support patentability absent a showing of criticality of the claimed range to the contrary. See M.P.E.P. § 2144.05, particularly subsections II and III. In this case, Deisseroth clearly teaches that 200 mM boric acid is effective as a buffer in tissue clearing compositions and Lai teaches the combination of N-methylglucamine with the conjugate salt of borate. Thus, the burden is shifted back to establish criticality of the claimed molar ratio of N-methylglucamine and boric acid and boric acid concentration by objective evidence.
Regarding claims 13, 15, and 35, the ‘931 patent discloses the water-soluble and lipid-soluble adjusting agents are refractive index adjusting agents (see claim 9 of the ‘931 patent). The disclosed water-soluble and lipid-soluble adjusting agents are the same as presently claimed, therefore their inherent properties, such as refractive index value would be within the claimed ranges.
Regarding claim 18, the ‘931 patent discloses the same lipid-soluble adjusting agents as claimed; therefore, inherent properties such as being miscible in water is obvious given the identical compounds.
Regarding claim 31, the ‘931 patent discloses a tissue clearing composition comprising one or more diluents (see claim 18 of the ‘931 patent).
Regarding claim 36, the ‘931 patent discloses the one or more diluents are selected from phosphate-buffered saline (pH 6.8-7.6) or tris hydrochloride buffer (pH 6.8-7.6) (see claim 22 of the ‘931 patent). Therefore, the ‘931 patent discloses the composition has a pH range from 6.8-7.6 given the addition of a buffer. It is noted that where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (See MPEP 2144.05 I).
Regarding claim 37, given the combined teaching and disclosure of Deisseroth and the ‘931 patent, the tissue clearing composition comprising a borate compound would inherently have improved tissue clearing capacity. See teachings above by Deisseroth.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the invention was filed.
Response to Arguments
Applicant's arguments on pages 7-16 of the reply have been fully considered, but not found persuasive of error over the modified grounds of rejection above and necessitated by the instant claim amendments. While the same prior art is applied, are cited and modified and new grounds of rejection are set forth above which fully address the instant claim amendments.
Applicant’s allegation that replacing hydrochloric acid with boric acid yields an unexpected result with respect to transparency of non-neural tissues on pages 9-13 of the reply is not found persuasive, as Lai clearly teaches tissue clearing compositions lacking hydrochloric acid as set forth above and Deisseroth clearly teaches sodium borate and boric acid as equivalent buffers in tissue clearing compositions. At this time, Applicant has not established the required nexus between the objective evidence of nonobviousness and the claimed composition; see M.P.E.P. § 716.01(b). While not cited in the obviousness rejection above, it is noted that Deisseroth contemplates clearing kidney tissue (¶0097), and so the preponderance of evidence does not support the allegation of unexpected results at this time. The fact that the inventor (may have) recognized another (potential) advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning on page 10 of the reply, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In this case, the argument is not persuasive because Applicant has not particularly pointed out with any specificity what elements of the modified obviousness rejection above could only have been gleaned from the instant Application.
In response to applicant's argument over Lai and Deisseroth on pages 13-15 of the reply, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, the arguments are not persuasive because Applicant appears to bodily incorporate the teachings of Deisseroth into Lai and which is an incorrect test for obviousness.
Applicant’s arguments regarding the double patenting rejections of record on page 16 of the reply are acknowledged, but not found persuasive of error.
Conclusion
No claims are allowed. No claims are free of the art.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN C BARRON whose telephone number is (571)270-5111. The examiner can normally be reached 7:30am-3:30pm EDT/EST (M-F).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached at 571-272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sean C. Barron/Primary Examiner, Art Unit 1653
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