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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/09/2025 has been entered.
Response to Amendments
Applicant's amendments filed 12/09/2025 to claims 1, 6, 21, 22, 25, 37, 39, and 52 have been entered. Claims 2-5, 7, 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, 51, and 52 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 Claims 38-43, 45, 47, 51, and 52 remain withdrawn from consideration. References not included with this Office action can be found in a prior action.
The instant amendments to claim have overcome the 35 U.S.C. § 103 rejections of record over Lai as evidenced Otanicar, which are withdrawn. Modified grounds of rejection are set forth below necessitated by the instant amendments.
The instant amendments to claim 1 have overcome the nonstatutory double patenting rejections over US 11,130,931 in view of Morikawa, which are withdrawn. Modified grounds of rejection are set forth below necessitated by the instant amendments.
Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and/or applicant’s comments.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 § 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; Reference A), and as evidenced by Otanicar (of record) and Tatham (of record).
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). 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 claim 8, Lai discloses homogenization occurs by protein denaturation by a denaturant or a homogenizing agent (p5, lines 11-18).
Regarding claims 21, 22, and 25, 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 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).
To reiterate, 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 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.
Although Lai suggests the use of borate compounds, the molar ratio of the borate compounds, particularly boric acid, to N-methylglucamine is not taught in sufficient specificity and therefore the instant rejection is made under obviousness.
However, it would have been obvious to one of ordinary skill in the art at the time the invention was made to look at the guidance provided by Lai and incorporate borate compounds, such boric acid or sodium borate. One would have been motivated to do so since Lai suggests the composition eliminates the need for sectioning of tissue, can enhance observation capability and signal detection sensitivity of cellular structures, and allows for three-dimensional viewing of the tissue in any orientation, and it is within the skill of an artisan to modify or optimize the composition depending on the desired effect. Therefore, if a skilled artisan wanted to adjust or modify the molar ratio of the borate compound to N-methylglucamine, one would have been motivated to utilize routine experimentation and optimization to achieve a desired molar ratio. See M.P.E.P. § 2144.05. As such, the burden is shifted back to Applicant to persuasively show nonobvious over the claimed molar ratios and reasonably commensurate to the scope of the claims.
Regarding claim 1, Lai does not teach boric acid (i.e. CAS number 10043-35-3).
Deisseroth teaches methods and compositions for preparing a biological specimen for microscopic analysis (Abstract). Deisseroth teaches boric acid as an exemplary buffer in compositions for tissue clearing (¶0054), reading on claim 1.
Deisseroth teaches methods and compositions for preparing a biological specimen for microscopic analysis (Abstract). Deisseroth teaches boric acid as an exemplary buffer in compositions for tissue clearing (¶0054), reading on claim 1.
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.
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, 20, and 22 of U.S. Patent No. 11,130,931 in view of Deisseroth et al. (US 2015/0144490; Reference A).
Although the claims are not identical, they are not patentably distinct from each other because:
Regarding claims 1 and 21, the ‘931 patent discloses a tissue clearing composition, comprising a homogenizing agent, a water-soluble adjusting agent, and a lipid-soluble adjusting agent, wherein the homogenizing agent is selected from the group consisting of N-methylglucamine and ethylenediamine; (b) the water-soluble adjusting agent is selected from the group consisting of iohexol, sodium thiosulfate, and polyethylene glycol; and (c) the lipid-soluble adjusting agent is selected from the group consisting of 2,2′-thiodiethanol and propylene glycol (see claim 1 of the ‘931 patent).
Regarding claim 1, the ‘931 patent does not claim the boric acid.
Deisseroth teaches methods and compositions for preparing a biological specimen for microscopic analysis (Abstract). Deisseroth teaches boric acid as an exemplary buffer in compositions for tissue clearing (¶0054), reading on claim 1.
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 claim 8, the ‘931 patent discloses the same group of homogenizing agents (see claim 1 of the ‘931 patent) The inherent properties of these agents as denaturants are maintained.
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.
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).
Regarding claims 22 and 25, given the teachings of Morikawa and the ‘931 patent’s disclosure of the use of triethanolamine-borate acid (see col. 9, lines 40-44), an ordinary artisan would recognize that boric acid as an obvious alternative to sodium tetraborate. An ordinary artisan would have reasonable expectation of success in using boric acid in the composition. See teachings above for the homogenizing agent, water-soluble adjusting agent, and lipid-soluble agent (also, see claims 3 and 6 of the ‘931 patent).
Regarding claim 23, 931’ discloses the concentration of each of N-methylglucamine, iohexol, and 2,2′-thiodiethanol ranges from 10% to 50% (see claim 4 of the ‘931 patent).
Regarding claim 26, the ‘931 patent discloses the concentration of each of N-methylglucamine and iohexol ranges from 10% to 50% and the concentration of propylene glycol ranges from 10% to 60% (see claim 5 of the ‘931 patent).
Regarding claim 28, 931’ discloses a tissue clearing composition consisting of a homogenizing agent, a water-soluble adjusting agent, a lipid-soluble adjusting agent, and one or more diluents, wherein (a) the homogenizing agent is urea; (b) the water-soluble adjusting agent is selected from the group consisting of iohexol, sodium thiosulfate, and polyethylene glycol; and (c) the lipid-soluble adjusting agent is selected from the group consisting of 2,2′-thiodiethanol and propylene glycol (see claim 18 of the ‘931 patent). See teachings above for boric acid.
Regarding claim 29, the ‘931 patent discloses the concentration of urea ranges from 5-50%, and the concentration of each of iohexol and 2,2′-thiodiethanol ranges from 10% to 50% (see claim 20 of the ‘931 patent).
Further regarding claims 1, 6. 23, 26, and 29, 931’ and Morikawa do not specifically teach the molar ratio of boric acid and N-methylglucamine or homogenizing agent. However, it would be easily obtained by an ordinary artisan through routine experimentation and optimization. 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 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 Morikawa and the ‘931 patent, the tissue clearing composition comprising a borate compound would inherently have improved tissue clearing capacity. See teachings above by Morikawa.
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 8-15 of the reply have been fully considered, but not found persuasive of error over the modified grounds of rejection set forth above. Briefly summarized, Deisseroth has been added to the 35 U.S.C. § 103 and nonstatutory double patenting rejections above and fully addresses the instant amendments to claim 1.
On pages 13-14 of the reply, Applicant alleges that the claimed composition yields unexpected results with respect to the clearing of kidney tissue. This is not found persuasive for several reasons. First, because the argument only appears to set forth that associated methods of use of the claimed composition are operable, which is not germane for considerations under 35 U.S.C. § 103 and the operability of the claimed composition has not been challenged under any 35 U.S.C. § 112(a) rejection. Deisseroth as cited makes clear that boric acid is an exemplary buffer in methods of and compositions for tissue clearing. Second, Applicant’s arguments are not persuasive because they are not reasonably commensurate to the scope of the claims; Applicant is claiming the composition and not any associated method of use and manipulative steps therein, and the composition claims are not limited to “OPTIclear A” (i.e. the composition set forth in the 1st paragraph of Example 1 of the specification). There is insufficient evidence of record to discriminate between expected vs. unexpected results, and if any alleged unexpected result is due to the inherent properties of the claimed composition vs. any particular combination of method steps in the disclosed methods of clearing any particular taxonomic species of kidney tissue.
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).
Applicant’s arguments regarding the double patenting rejections of record on page 15 of the reply are acknowledged, but not found persuasive of error.
Conclusion
No claims are allowed. No claims are free of the art.
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/Sean C. Barron/Primary Examiner, Art Unit 1653