DETAILED ACTION
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 .
Claim Status
Claim 1 was amended, claim 2 was canceled, and claims 17-21 were newly added in the response filed 1/15/2026. Claims 1 and 3-21 are pending. Claims 4-16 remain withdrawn. Claims 1, 3, and 17-21 are under examination.
Claim Objections
The amendments are persuasive to overcome the objection of record to claim 1 on p. 3 of the OA dated 10/16/2025; therefore, the objection is withdrawn.
Claim 21 is objected to because of the following informalities: in line 2, the indefinite article “a” should be inserted before the word “single”.
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(d)
The amendments to claim 1 are persuasive to overcome the 35 USC 112(d) rejection of record over claim 3 on p. 3 of the OA dated 10/16/2025; therefore, the rejection is withdrawn.
New Claim Rejections - 35 USC § 112(a)-New Matter
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, 3, and 17-21 are 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 was broadened to remove the requirement that the solvent for the reaction is D2O. There does not appear to be support in the disclosure as filed for the broadening. The specification only contemplates D2O as the solvent.
Newly introduced independent claim 18 introduces a process that produces D-DSePA in ≥ 42% yield. There does not appear to be support in the disclosure as filed for yields above 42%. The only example in the specification teaches a yield of 42% and there are no general teachings in the specification as filed regarding ranges of yields that can be obtained.
Modified Claim Rejections - 35 USC § 103-Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. See p. 4-8 of the OA dated 10/16/2025 regarding the rejection of record.
Claim(s) 1, 3, and 17-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kumwar (“3,3’-Diselenodipropionic acid (DSePA): A redox active multifunctional molecule of biological relevance” BBA – General Subjects 1865, 2021, p. 129768, available online 10/24/2020, of record), in view of Jain (“Preparation of Organoselenium Compounds” BARC/2009/I-003, published 2009); Rao (“Deuterated Drugs” Pharmaceutical Chemistry Journal, 55, 12, March 2022; doi: 10.1007/s11094-022-02584, of record) and CAS RN 1219799-25-3 (entered into STN on 4/21/2010, of record).
Applicant Claims
Applicant claims a method of synthesis of organodiselenide derivative 3,3’-diselenodipropionic acid-D8 (D-DSePA) comprising:
adding sodium borohydride (NaBH4) to a suspension of selenium powder (Se) with stirring to form a sodium selenide (Na2Se2) solution and heating the Na2Se2 solution at about 60°C for 30 min; and
cooling the sodium selenide (Na2Se2) solution to room temperature and adding and 3-bromopropionic acid-D4 with stirring to form D-DSePA, preferably in D2O solvent.
Determining the Scope and Content of the Prior Art (MPEP §2141.01)
Kumwar teaches that 3,3’-diselenodipropionic acid (DSePA) is a redox active multifunctional molecule of biological relevance and provides a review of research on DeSEPA. See abstract. DSePA is of the following formula:
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. See p. 2, second col.
Kumwar further teaches that DSePA is prepared by reacting aqueous Na2Se2 with 3-bromo or 3-chloropropionic acid. See section 2 on p. 2:
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. Thus, Kumwar teaches that the sodium diselenide is prepared by reduction of selenium with sodium borohydride (NaBH4). Jain corresponds to reference [44] of Kumwar (see p. 11 of Kumwar), discussed in the above section.
Kumwar additionally teaches that major conclusions from the review are that: “It is an interesting diselenide structurally related to selenocystine. It shows moderate glutathione peroxidase (GPx)-like activity and is an excellent scavenger of reactive oxygen species (ROS). Exposure to radiation, as envisaged during radiation therapy, has been associated with normal tissue side effects and also with the decrease in selenium levels in the body. In vitro and in vivo evaluation of DSePA has confirmed its ability to reduce radiation induced side effects into normal tissues. Administration of DSePA through intraperitoneal (IP) or oral route to mice in a dose range of 2 to 2.5 mg/kg body weight has shown survival advantage against whole body irradiation and a significant protection to lung tissue against thoracic irradiation. Pharmacokinetic profiling of DSePA suggests its maximum absorption in the lung.” See abstract. Also see section 9 on p. 10-11, which includes Fig. 6:
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.
As indicated above Jain corresponds to reference [44] of Kumwar (see p. 11 of Kumwar). Kumwar describes that reference teaches the preparation of DSePA using 3-bromopropionic acid in aqueous Na2Se2 obtained by reduction of selenium by NaBH4. See first paragraph in section 2 on p. 2 of Kumwar. DSePA is referred to as compound (11) in Jain:
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. See Scheme 1 on p. 2. Jain teaches the experimental procedure for compound 11 on p. 6:
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“To a suspension of selenium powder (3.0 g, 37.9 mmol) in water (100 ml) sodium borohydride (1.44 g, 39.9 mmol) was added carefully at room temperature with stirring. Selenium got consumed and the orange brown solution of Na2Se2 (Scheme -4) was warmed at 60 °C for half an hour (30 min). The reaction mixture was allowed to cool to room temperature to which 3-bromopropionic acid (5.79 g, 37.9 mmol) was added and as the reaction proceeded within 10 min a bulky pale-yellow precipitate was appeared which was stirred further for 2 h. Later the aqueous work up was followed by extraction with diethyl ether (3 x 50 ml) which on evaporation in vacuo gave a pale-yellow product which was recrystallized from diethyl ether-hexane to give an off-white crystalline compound (yield 4.8 g, 83%)”.
Thus, Jain explicitly teaches all of the experimental conditions of instant claims 1 and 3 for non-deuterated DSePA.
Rao is a recent review on deuterated drug molecules. Rao teaches that replacement of hydrogen atoms for deuterium atoms is an extremely useful tool for the enrichment of drug’s metabolism. Specifically, Rao teaches: “Selective replacement with deuterium leads to amplified bond strength which in turn increases the biological half-life and thus metabolic stability of the drug. Furthermore, deuterium substitution may also result in metabolic shunting leading to decreased exposure of critical organs to unwanted and toxic metabolites or increased exposure to desired active metabolites. This article focuses on numerous illustrations where deuteration came up with improvement of metabolic stability of drug and reduction in toxicity relative to the untreated drug while retaining its substantial pharmacological profile. Deuterated edition of present drugs can demonstrate better pharmacokinetic or toxicological properties due to stronger deuterium–carbon bonds by altering their metabolism and hence are a subject of major research”. See abstract. Rao teaches a list of deuterated drugs which have been either approved for therapeutic use by the FDA or are in clinical trials. See bottom of p. 1374.
CAS RN 1219799-25-3 is a reference that teaches that 3-bromoprionic acid-D4 of the following formula:
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was known to the person of ordinary skill in the art since 2010.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Kumwar does not explicitly teach or suggest 3,3’-diselenodipropionic acid-D8, the claimed deuterated analog of DSePA, or its preparation.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Kumwar, Jain, Rao, and CAS to arrive at the instantly claimed method with a reasonable expectation of success before the effective filing date of the instant invention. A person of ordinary skill would have been motivated to modify the DSePA of Kumwar and Jain to arrive at the claimed D-DSePA deuterated analog because Kumwar teaches that DSePA is a known molecule with desirable bioactivity and Rao teaches that deuteration of bioactive molecules is a useful tool for the enrichment of the drug’s metabolism. The skilled artisan would have been further motivated to prepare D-DSePA according to the claimed method because it is the same method as used in Kumwar and Jain, except that 3-bromopropionic acid is substituted for 3-bromopropionic acid-D8 and H2O is substituted for D2O. Further CAS teaches that 3-bromopropionic acid-D8 is known in the art.
Therefore, the skilled artisan would be motivated to prepare D-DSePA using the known procedure and known deuterated materials of Kumwar, Jain, and CAS to predictably arrive at a deuterated analog of a known bioactive compound, which Rao teaches is a known modification in the art to favorably alter the metabolic stability of bioactive compounds. Also see MPEP 2143(I)(B) and MPEP2143(I)(C).
Regarding claims 17-21, Jain teaches that sodium diselenide is reacted with 3-bromopropionic acid in 100 mL water (H2O) at room temperature for about 2 hours to produce a pale-yellow precipitate, which is then extracted with diethyl ether (3 x 50 mL), subjected to evaporation under vacuum (in vacuo) to give a pale-yellow product which was recrystallized from diethyl ether-hexane to give an off-white crystalline compound in 83% yield and having a melting point of 140°C. Kumwar further teaches that DSePA is a cream-colored solid which can be crystallized from acetone, ethyl acetate, diethyl ether-hexane (Jain), or hot water. See first paragraph of section 2 on p. 2.
Neither Jain nor Kumwar explicitly teach that the D-DSePA product is obtained with a yield of 42% and a melting point of 128°C (claims 17 and 18); that the diethyl ether extracting solvent is employed in a diethyl ether:reaction mixture (v/v) ratio of 1:5.5 (claim 19); that the evaporated product is washed two times with hexane in a 1:5.5 v/v ratio with respect to the reaction mixture to remove organic impurities (claim 21); wherein the method further comprises generating a single crystal structure of D-DSePA (claim 22); and wherein the Na2Se2 and 3-bromopropionic acid-D4 are stirred overnight at room temperature (claim 18).
Regarding the use of a washing solvent, a skilled artisan would have found it prima facie obvious to wash the evaporated solid with an organic solvent, which will not dissolve said solid, to remove organic impurities. The extraction of the DSePA into the diethyl ether will predictably separate the DSePA from the aqueous reaction mixture and any impurities soluble therein; however, but not organic impurities soluble in diethyl ether, which will be recognized by any person of ordinary skill in the art. Therefore, it is obvious to do a wash with an organic solvent that DSePA is insoluble in, which necessarily must be different from the extraction solvent, to remove said organic impurities. It would be further obvious to use employ hexane as the washing solvent because it is used as an anti-solvent in the recrystallization as taught by Kumwar and Jain. As the DSePA was extracted into the diethyl ether, it is obvious that DSePA must be soluble in the diethyl ether and recrystallizing the compound would require the use of a DSePA insoluble solvent and/or a mixture of a DSePA soluble solvent and an anti-solvent, which the DSePA is insoluble in. Jain teaches that DSePA is insoluble in hexane and thus the skilled artisan would recognize that hexane is a suitable organic solvent for washing and retaining a solid product for recrystallization. Further, the hexane is carrying out the same function in the recrystallization of removing hexane soluble impurities while serving as an anti-solvent. Thus, a washing step can also be considered to be a reordering of process steps to pre-purify the crude evaporated product before it is subjected to recrystallization, which should predictably produce a purer product. D-DSePA would be expected to possess similar properties to those of DSePA as the only difference between the two is that some hydrogen atoms are substituted for their deuterium isotopes, therefore there is a reasonable expectation of success that all of the solvents employed in Kumwar and Jain would also be applicable to a process for producing the structurally similar deuterated compound. Also see MPEP 2144.09.
Regarding the v/v ratios of the extracting and washing solvent to the reaction mixture volume, Jain teaches that the ratio of the extraction is 50 mL diethyl ether : 100mL reaction mixture, or 1:2. Thus Jain teaches the use of a larger volume of extracting solvent than that claimed. However, it would be prima facie obvious to modify the volume of extracting and washing solvent to fall closer to the claimed range because using less extracting solvent in an extraction is more efficient. Less energy is required to be expended removing the solvent from the mixture and the process generates less solvent waste. Further, the volume of the solvents does not appear to be critical to the outcome of the extraction and washing steps. Regarding extraction, as long as the amount of solvent is sufficient to dissolve the product (DSePA), then the DSePA will be predictably extracted into the organic layer. If not enough extracting solvent is used to recover the DSePA from the aqueous layer, the skilled artisan would then predictably use a larger volume of solvent. The same rationale applies to the washing step. As long as enough solvent is used to wash the crude solid to remove impurities, then the washing step will predictably remove said impurities from the crude solid. To summarize, both of these volume/volume ratios do not appear to be critical and can be predictably optimized using routine optimization. Also see MPEP 2144.05.
Regarding the yield, melting point, and crystal structure of the D-DSePA product, as the combined teachings of Kumwar, Jain, and Rao teach or suggest all limitations of the claimed process, then the skilled artisan would expect that the D-DSePA product obtained would be obtained in similar yields to that claimed and with similar properties to those claimed. Also see MPEP 2144.09 and MPEP 2112.01. Jain explicitly teaches that DSePA is obtained from the process in 83% yield, so there is a reasonable expectation of success of obtaining a significant amount of D-DSePA from the combined process of Kumwar, Jain, and Rao. This rationale is further supported by the specification as filed, which teaches that when all of the claimed limitations are met and the recrystallization solvent is a mixture of diethyl ether and hexane, then the product produced has a single crystal structure possessing the claimed melting point.
Regarding the reacting of Na2Se2 and 3-bromopropionic acid-D4 in D2O solvent overnight at room temperature, Jain teaches that the reaction to DSePA can be completed in about 2 hours at room temperature. Though neither Jain nor Kumwar explicitly teach stirring overnight, it would have been prima facie obvious for the skilled artisan to lengthen the reaction time if the reaction was not complete in 2 hours. The skilled artisan could predictably arrive at the claimed reaction time though routine optimization. Further, the claimed reaction time does not appear to be critical to the outcome of the reaction. Also see MPEP 2144.05.
Applicant Arguments on p. 7-11 of the response filed 1/15/2026
The Applicant argues that Kumwar does not explicitly teach “heating the Na2Se2 solution at about 60°C for 30 minutes; and cooling the Na2Se2 solution to room temperature and adding 3-bromopropionic acid” and that this deficiency is not cured by Rao. This argument has been fully considered but is not persuasive. Though there does not appear to be any criticality attached to the temperatures and reaction time based on the specification as filed, Jain is added to explicitly teach these limitations. Therefore, these conditions are known in the art and the Applicant’s arguments are not persuasive.
The Applicant further argues that neither Kumwar nor Rao teach the limitations of new claims 17-21. This argument has been fully considered but is not persuasive. The inclusion of Jain into the rejection and the discussions of each claim above address all of the claimed limitations. The arguments that Kunwar teaches that DSePA is produced with a different melting point and/or yield than that claimed and as such cannot render the instant D-DSePA yields and melting point obvious are unpersuasive. As explained in the rejection, the rejection is based on a combination of three references and as the combination of references teaches or suggests all of the process limitations, then the product produced from the combined process is expected to possess similar properties and prepared in a similar yield to that claimed. Jain teaches the same conditions as those claimed with minor differences in the time of reaction, the v/v ratio of the extracting solvent to reaction mixture, and the inclusion of a washing step-none of which appear to be critical to the outcome of the reaction. Notably, Jain also teaches the same recrystallization conditions as those in the specification as filed. Therefore, a product produced from the combined reaction and recrystallized from the solvent system of Jain is expected to possess the claimed crystal structure having the claimed melting point. Therefore, the Office maintains that the claimed processes are prima facie obvious in view of the teachings of the cited prior art.
Conclusion
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.
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/AMY C BONAPARTE/Primary Examiner, Art Unit 1692