Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Claims 1-13 of J. Liu, et.al. US 18/242,314 (09/05/2023) are pending. Claims 1 and 13 are withdrawn as directed to unelected Groups I and III. Claims 2-12 are under examination on merits and are rejected.
Requirement for Election of Invention
There are two criteria for a proper requirement for restriction between patentably distinct inventions: (A) The inventions must be independent or distinct as claimed; and (B) There would be a serious burden on the examiner if restriction is not required. MPEP § 803(I). In the instant case, restriction to one of the following inventions is required under 35 U.S.C. 121:
Invention Election
Restriction to one of the following inventions is required under 35 U.S.C. 121:
Claim 1, drawn to a compound having a structure as shown in the formula I, classified in C07C 211/51;
Claims 2-12, drawn to a method for preparing the compound of the formula I according to Group (I), classified in C07C209/68; and
Claim 13, drawn to method for preparing a deuterated drug, comprising using the compound of the formula I according to Group (I), classified in C07B 2200/05.
Distinctness Among Inventions I-III
Inventions I and II are related as process of making and product made. The inventions are distinct if either or both of the following can be shown: (1) that the process as claimed can be used to make another and materially different product or (2) that the product as claimed can be made by another and materially different process (MPEP § 806.05(f)). In the instant case, the claimed product can be prepared with a different process, for example, Ernstbrunner teaches that the claimed compound the formula I can be prepared by reacting of 1,4-phenylenediamine with CH3OD or D2O. See E. E. Ernstbrunner, et al. 10.1, Journal of Raman Spectroscopy 161-168 (1981)(“Ernstbrunner”) at page 161, right col. Experimental, paragraph 2, line 8-10. Therefore, Inventions I and II are distinct.
Inventions I and III are related as product and process of use. The inventions can be shown to be distinct if either or both of the following can be shown: (1) the process for using the product as claimed can be practiced with another materially different product or (2) the product as claimed can be used in a materially different process of using that product. See MPEP § 806.05(h). In the instant case, the claimed product can be used for a different process for example as an starting material to form a polymer [see J. Stejskal, 41, Progress in Polymer science, 1-31 (2015)(“Stejskal”)]. Therefore, Inventions I and III are distinct.
Inventions II and II are directed to related processes. The related inventions are distinct if: (1) the inventions as claimed are either not capable of use together or can have a materially different design, mode of operation, function, or effect; (2) the inventions do not overlap in scope, i.e., are mutually exclusive; and (3) the inventions as claimed are not obvious variants. See MPEP § 806.05(j). In the instant case, the inventions as claimed processes have different materially design and not overlap in scope. Furthermore, the inventions as claimed do not encompass overlapping subject matter and there is nothing of record to show them to be obvious variants.
Search Burden
There would be a serious search and/or examination burden if restriction were not required because one or more of the following reasons apply:
The inventions have acquired a separate status in the art in view of their different classification;
The inventions have acquired a separate status in the art due to their recognized divergent subject matter; and/or
The inventions require a different field of search (e.g., searching different classes/subclasses or electronic resources, or employing different search strategies or search queries).
In the instant case, the claimed inventions leading to generally complicated searching within multiple data bases, including electronic compound databases, such as CAPLUS and CASREACT (See https://www.cas.org) and Similarity for the claimed compound and the claimed method; and a keyword searches in Google Scholar, general literature and books regarding deuterated drugs and using of compounds for the preparation of deuterated drugs. Patents need not be cited to show different fields of search. MPEP § 808.02.
Burden and Traversal of the Restriction Requirement
Applicant is advised that the reply to this requirement to be complete must include (i) an election of an invention to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected invention.
The election of an invention may be made with or without traverse. To reserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the restriction requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Joint Inventors
Applicant is reminded that upon the cancelation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
Potential Rejoinder
The examiner has required restriction between product claims and process claims. Where applicant elects claims directed to the product, and all product claims are subsequently found allowable, withdrawn process claims that include all the limitations of the allowable product claims should be considered for rejoinder. All claims directed to a nonelected process invention must include all the limitations of an allowable product claim for that process invention to be rejoined.
In the event of rejoinder, the requirement for restriction between the product claims and the rejoined process claims will be withdrawn, and the rejoined process claims will be fully examined for patentability in accordance with 37 CFR 1.104. Thus, to be allowable, the rejoined claims must meet all criteria for patentability including the requirements of 35 U.S.C. 101, 102, 103 and 112. Until all claims to the elected product/apparatus are found allowable, an otherwise proper restriction requirement between product/apparatus claims and process claims may be maintained. Withdrawn process claims that are not commensurate in scope with an allowable product/apparatus claim will not be rejoined. See MPEP § 821.04. Additionally, in order for rejoinder to occur, applicant is advised that the process claims should be amended during prosecution to require the limitations of the product/apparatus claims. Failure to do so may result in no rejoinder. Further, note that the prohibition against double patenting rejections of 35 U.S.C. 121 does not apply where the restriction requirement is withdrawn by the examiner before the patent issues. See MPEP § 804.01.
Election over the Phone
Examiner discussed the Restriction/ Election requirement during the phone interview with Kirk A. Wilson on 02/04/2026. Pursuant to the restriction requirement, Applicant elected Group II (claims 2-12), without traverse, during the phone interview on 02/04/2026. Claims 1 and 13 drawn to non-elected Group(I), (III) are withdrawn from consideration pursuant to 37 CFR 1.142(b).
Applicant is required to confirm the election in the reply to this Office action.
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.
Claims 2-12 are rejected under 35 U.S.C. 103 E. E. Ernstbrunner, et al. 10.1, Journal of Raman Spectroscopy 161-168 (1981)(“Ernstbrunner”) in view of D. D. Perrin, et al, pKa prediction for organic acids and bases. Vol. 1. London: Chapman and Hall, (1981)(“Perrin”), N. Aeamsuksai, et al. 24.6 Engineering Journal 63-77 (2020)(“ Aeamsuksai”) and W. Li, et al. 14.3 Nature Chemistry 334-341 (2022)(“Li”).
E. E. Ernstbrunner, et al. 10.1, Journal of Raman Spectroscopy 161-168 (1981)(“Ernstbrunner”)
Ernstbrunner teaches a method for preparation of d4-N,N, N’,N’-PPD1 through dissolution of PPD in CH3OD or in D2O. Ernstbrunner at page 161, right col. Experimental, paragraph 2, line 8-10. Herein CH3OD /D2O is both the solvent and deuterated reagent.
The Ernstbrunne method comprises:
(i). dissolving 1,4-diaminobenzene in a deuterated solvent that is CH3OD or D2O; and
(ii). adding a deuterated reagent that is CH3OD or D2O and subjecting the mixture solution to deuteration reaction.
Difference between Ernstbrunne and the Claims
Ernstbrunne differs from the instant claim 2 in that:
(i). Ernstbrunne does not teach to add a catalyst in sequence with the deuterated reagent;
(ii).Ernstbrunne does not teach conduct the deuteration reaction under a protective atmosphere; and
(ii). Ernstbrunne does not teach to repeat steps (1) and (2) three times sequentially.
D. D. Perrin, et al, pKa prediction for organic acids and bases. Vol. 1. London: Chapman and Hall, (1981)(“Perrin”)
Perrin teaches that
An acid is ‘a species having a tendency to lose a proton’ (Bronsted, 1923) while a base is ‘a species having a tendency to add on a proton’. Hence for every acid, HA, there is a conjugate base, A- :
PNG
media_image1.png
65
557
media_image1.png
Greyscale
and for every base, B, there is a conjugate acid, BH+:
PNG
media_image2.png
52
545
media_image2.png
Greyscale
Thus, acetic acid-acetate ion and ammonium ion-ammonia are examples of conjugate acid-base pairs. If HA ( or BH +) has a great tendency to lose protons, it follows that its conjugate, A- (or B), has only a small tendency to accept protons. In other words, if HA (or BH +) is a strong acid, A- ( or B) is a weak base, and vice versa.
Acids and bases so defined can only manifest their properties by reacting with bases and acids respectively. In aqueous solution, acids react with water acting as a base:
PNG
media_image3.png
71
744
media_image3.png
Greyscale
and bases react with water acting as an acid:
PNG
media_image4.png
48
741
media_image4.png
Greyscale
Quantitatively, the acid strength of HA, or BH+, relative to the base strength of water is given by the equilibrium constant expression for Equation (1.3):
PNG
media_image5.png
83
752
media_image5.png
Greyscale
where parentheses denote activities.
As almost all measurements are made in dilute aqueous solution, the concentration of water remains essentially constant and its activity can be taken as unity. Letting H+ represent the solvated proton, we have Ka = (H +)(B}/(A), where Ka is the acidic dissociation (or ionization) constant, and B and A represent base and acid species, respectively. This equation can be written in the form
PNG
media_image6.png
52
610
media_image6.png
Greyscale
where pKa is the negative logarithm of Ka, and is equal to the pH at which the activities of A and B are equal.
Equation (1.6) also expresses the strength of the conjugate acid of an organic base (commonly spoken of as 'the pKa of the organic base', the 'basic pKa.' or 'the pK for proton addition'). Thus pKa. = 9.25 for the ammonium ion lies on the same scale as pKa = 4. 76 for acetic acid and 10.00 for phenol. The greater the pKa value, the weaker the substance as an acid, or, conversely, the stronger is its conjugate base. For any given solvent, the pKa scale is convenient for expressing the strengths of both acids and bases.
Perrin at chapter one, page 1-2, the concept of pKa, paragraph 1, emphasis added.
Perrin teaches that pKa of methanol is 15.5, which is higher than the pKa of water that is 14. Perrin at Table 2 and Eq. 1.8.
Thus, Perrin fairly teaches one ordinary skill that methanol is a weak acid and it has a weak ability to dissociate its proton; Water as follows:
PNG
media_image7.png
87
714
media_image7.png
Greyscale
Therefore, one ordinary skill would be appraised that Ernstbrunne deuteration method of reacting of 1,4-diaminobenzene in CH3OD to prepare of d4-N,N,N’,N’-1,4-diaminobenzene would be slow because the dissociation of D+ from CH3OD also is slow.
N. Aeamsuksai, et al. 24.6 Engineering Journal 63-77 (2020)(“Aeamsuksai”)
Aeamsuksai that there is a reversible reaction between methanol and sodium hydroxide to form NaOCH3 and H2O as expressed in Eq. (1).
CH3OH + NaOH ↔ NaOCH3 + H2O (1)
and it is assumed that a hydroxide-methoxide ionic equilibrium (Eq. (2)) is achieved once CH3OH and NaOH species are mixed.
CH3OH + OH- ↔ CH3O- + H2O (2)
Aeamsuksai at page 64, right col. right col. 2.1 Reaction Model. Line 1-7, emphasis added.
Thus, Aeamsuksai teaches that hydroxide (OH-) can quickly transfer methanol into water and CH3O- in an equilibrium manner.
W. Li, et al. 14.3 Nature Chemistry 334-341 (2022)(“Li”)
Li teaches that isotope labelling, particularly deuteration, is an important tool for the development of new drugs, specifically for identification and quantification of metabolites. Li at abstract.
Li teaches that:
Deuterium-labelled compounds show virtually identical physical behavior to that of their hydrogen analogues, whilst differing in molecular mass, and thus are the primary source for the preparation of internal standards for liquid chromatography–mass spectrometry (LC–MS) analysis in the investigation of environmental, animal and human samples. Accordingly, deuteration facilitates advancements in metabolomics including metabolite identification and quantification, in toxicogenomic studies for the related reactive metabolites and in proteomics studies.
Li at page 334, left col. paragraph 1, line 9-the last sentence.
Li also teaches that:
there is growing potential and interest in accessing selectively deuterated building blocks on a larger scale. In this context, specific and practical labelling methodologies for arenes/heteroarenes as well as amines, which are found in most small-molecule-based drugs, are of increasing importance.
Li at page 334, left col. paragraph 2, line 8-14, emphasis added.
Given 1,4-diaminobenzene is an often used building blocks in drug discovery [ for example, J .L. Vique‐Sánchez, et al, 7(27), ChemistrySelect, e202202301, (2022)(“Vique‐Sánchez”) for PIK3CA Inhibitor C-5 and R. He, et al, 6.7 ACS medicinal chemistry letters 782-786, (2015)(“He”) for SHP2 inhibitor Compound 2 as indicated below], therefore, Li provides a motivation to prepare d4-N,N, N’,N’-1,4-diaminobenzene as a building block for drug discovery (such as PIK3CA Inhibitor and/or SHP2 Inhibitor).
PNG
media_image8.png
462
1715
media_image8.png
Greyscale
Obviousness Rationales of the Claims
One ordinary skill seeking d4-N,N, N’,N’-1,4-diaminobenzene, through deuteration of 1,4-diaminobenzene with CH3OD, as a building block for drug discovery (such as PIK3CA Inhibitor and/or SHP2 Inhibitor), is motivated to modify the Ernstbrunne method by:
(i). adding a base such as NaOD to the solution of 1,4-diaminobenzene in CH3OD; and
(ii). conducting the deuteration reaction under a protective atmosphere.
One ordinary skill has a motivation to do so with a reasonable expectation of success because:
(i). Ernstbrunner teaches that d4-N,N, N’,N’-1,4-diaminobenzene can be prepared through dissolution of 1,4-diaminobenzene in CH3OD.
(ii). Perrin teaches that methanol is a weak acid, it has a weak ability to dissociate its proton; water has a stronger ability to dissociate its proton compared to methanol;
(iii). Aeamsuksai teaches that NaOH can quickly transfer methanol into water and CH3O- in an equilibrium manner;
(iv). using of NaOD instead of NaOH can increase the deuterium level of the reaction mixture and prompt the process of deuteration reaction; and
(v).Conduction of the reaction under a protective atmosphere can exclude water (H2O) from air into the reaction mixture.
One ordinary skill is also motivated to further modify the proposed method by removing of the solvent after some time of the reaction and then adding fresh CH3OD to conduct the reaction under a protective atmosphere for several times such as 3 time, thus arrive at a method meeting each and every limitation of claims 2, 5 and 7, therefore, claims 2,5 and 7 are obvious.
One ordinary skill has a motivation to do so with a reasonable expectation of success because H2O and HDO are formed as byproducts during the reaction is processed as indicated below, which would slow down the deuteration reaction.
PNG
media_image9.png
582
1136
media_image9.png
Greyscale
With regard the claimed 3 times, [w]here 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 unless there is evidence indicating such ranges is critical. MPEP § 2144.05(II)(A). Herein, the application dos not provide evidence to show the claimed 3 times is critical. Therefore, claims 2,5 and 7 are obvious.
Claim 3 is obvious because one ordinary skill is motivated to further modify the proposed method by adding CDCl3 as a solvent because 1,4-diaminobenzene is soluble in chloroform. See TCI AMERICA for 4-Phenylenediamine (2018) at page 3 of 5, Solubility.
Claims 4, 6, 8-12 are obvious because one ordinary skill is motivated to optimize the reaction conditions of the proposed method including the molar/weight ratio among each of the reacting materials and the temperature of reaction into the claimed ranges. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. MPEP § 2144.05(II)(A) (citing In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) ("[w]here 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”)). Herein, the application dos not provide evidence to show the claimed ranges are critical for the claimed method. Rather one ordinary skill has a motivation to optimize the reaction condition to prompt of the deuteration reaction.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANK S. HOU whose telephone number is (571)272-1802. The examiner can normally be reached 6:30 am-2:30 pm Eastern on Monday to Friday.
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, Scarlett Goon can be reached at (571)2705241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FRANK S. HOU/Examiner, Art Unit 1692
/ALEXANDER R PAGANO/Primary Examiner, Art Unit 1692
1 1,4-diaminobenzene, See Ernstbrunner Abstract; d4-N,N,N,N'-PPD should be a typo and it should be d4-N,N,N’,N'-PPD