Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
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Applicant ignores the following found in the previous action
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See section under 112-2, for consequence of overlooking Examiner’s request.
Claims 17, 28-30, 31, 32, 36, 39 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/24/2026.
Claim Rejections – Improper Markush Group
The nonstatutory Markush grouping rejection is based on a judicially approved “improper Markush grouping” doctrine. Claims 1-7, 9-11, 13 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature.
A Markush claim contains an “improper Markush grouping” if:
(1) the species of the Markush group do not share a single structural similarity,”
OR
(2) the species do not share a common use.
Members of a Markush group share a "single structural similarity” when they belong to the same recognized physical or chemical class or to the same recognized physical or chemical class or to the same art-recognized class. Members of a Markush group share a common use when they are disclosed in the specification or known in the art to be functionally equivalent (see Federal Register, Vol. 76, No. 27, Wednesday, February 9, 2011, p. 7166, left and middle columns, bridging paragraph).
The compounds do not even belong to a recognized single class of compounds because every variable varies having complex meanings and endless permutations and combinations.
Consider for example, except for the small structural portion
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, rest of the claimed formula of claim 1 is drawn to structural possibilities defined with generic terms, and drawn to unknown structural possibilities that defy commonsense. The members of the recited Markush group are so disparate chemically as not to be members of a recognized chemical class of compounds. Further the point of attachment and how these are linked to each render the conceivable compounds structurally different. In view of these claimed elements and the divergent substitutions on the above groups, the physical and chemical properties of claimed compounds are going to be different. Applicants’ may have to establish the core structure for their claimed compound. It cannot be said that all members of the Markush group have a single structural similarity, based on the above described structural differences. Specifically, the species of the Markush group do not share a “single structural similarity” because there are no required structural features within each variable definition such that each member of the group would have at least one structural feature, which feature is essential to the activity/function of the claimed compounds, in common. In addition alternatively usable member of the Markush group for example, the inhibitors or binders of different enzymes, does not share a common use, absent evidence to the contrary.
The question of whether the lack of a specific statutory basis is a fatal flaw against a holding of an Improper Markush group was decided in In re Harnish, 206 USPQ 300, 305, where the court said, “…we think it should be clear from our actions in Weber and Haas II that we there recognized the possibility of such a thing as an "improper Markush grouping." We were and are aware that it does not have a specific statutory basis …” The court went on to reverse the rejection, (which had been made by the Board under Rule 196(b)) but not on the lack of a specific statutory basis but rather, “Clearly, they are all coumarin compounds which the board admitted to be "a single structural similarity." We hold, therefore, that the claimed compounds all belong to a subgenus, as defined by appellant, which is not repugnant to scientific classification. Under these circumstances we consider the claimed compounds to be part of a single invention so that there is unity of invention…” Thus, the rejection was overturned not because of any lack of a specific statutory basis, but because of the specific facts in the case. The Markush group was held proper in that case, as was the case also in Ex parte Price 150 USPQ 467, Ex parte Beck and Taylor, 119 USPQ 100, and Ex parte Della Bella and Chiarino 7 USPQ2d 1669. Cases where the Markush group was held improper include Ex Parte Palmer, 7 USPQ 11, In re Winnek, 73 USPQ 225, In re Ruzicka, 66 USPQ 226, Ex parte Hentrich, 57 USPQ 419, Ex parte Barnard, 135 USPQ 109, Ex parte Reid, 105 USPQ 251, Ex parte Sun and Huggins, 85 USPQ 516, In re Thompson and Tanner, 69 USPQ 148, In re Swenson, 56 USPQ 180, and In re Kingston, 65 USPQ 371. Note In re Milas 71 USPQ 212 in which the structural difference between vitamin A and D was sufficient to uphold the improper Markush rejection. Also see In re Winnek 73 USPQ 225 and In re Ruzicka 66 USPQ 226 in which structural differences were small and yet a similar holding was maintained. All these cases involved compounds in the pharmaceutical art known to be structure-sensitive. Of particular interest is Ex Parte Hozumi, 3 USPQ2d 1059, which reversed an improper Markush rejection “in view of the relatively large proportion of the structure of the compounds in the claimed class which is common to the entire class”. Here, by contrast, the amount in common is none.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
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 1-7, 9-13 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 claims are drawn to prodrugs. The term ‘prodrug’ implies that the claimed compounds are reversed in vivo to a drug. Note that a prodrug is an inactive or less active compound that must undergo a chemical or metabolic transformation inside the body (in vivo) to become an active pharmacological drug.
What drugs are intended here is unclear, rendering the scope of the claim 1 unclear.
Further the formula of claim 1 is drawn to commonsense defying structures akin to impossible substituents. Consider for example, in
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X1’=X’2=R3’=H, L1=L2=L3=bond, R3=aryl would mean the intended compound is
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. It is unclear what this compound would be a prodrug for.
Further L1, L2 or L3 are defined in vague terms such as ‘alkyl’ a monovalent term. How a monovalent moiety can link two groups is unclear.
Note that if a substituent is impossible, the claim can properly be rejected under 35 USC 112 paragraph 1 or 2. ... A compound with an impossible substituent clearly cannot be made, and hence a paragraph 1 rejection is proper.
Dependent claims do not solve the problems of the base claim. As such all the claims are rejected as well.
Claim 12 depends on claim 1 and lacks antecedent basis, because the recited compound of claim 12 partial structure shown below,
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lacks the necessary attachments, as defined for the corresponding C in the claim 1 formula partial structure shown below:
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as per the definition of L3, R’3 and R3 in claim 1
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With R’3 in claim 12 is H, R3 as defined is not a vinyl group.
See rejection under Claim Rejections - 35 USC § 102.
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.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18293171
(reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the compound of conflicting claim is drawn to overlapping subject matter as explained below.
Claim 1 of 18293171 is drawn to compound having the following partial structure.
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The difference is that in the instant case R3 group which as defined is aryl or heteroaryl. In the conflicting case it is the corresponding claim it is alkyl (methyl).
The compounds in both cases are as per disclosures are prodrugs,
Throughout the recitation in the instant claims, alkyl and aryl are interchangeable to make dithioketal prodrugs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim Rejections - 35 USC § 112
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 1-7, 9-11,13 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for one possibility of a prodrug compound of the given formulae (here in after formula), does not reasonably provide enablement for large number of possibilities conceivable for the formula. For example, it is not seen wherein the specification enabling disclosure is found for any of L1, L2 or l3 is an amino, or all L1, L2 or l3 is a bond. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the relevant factual considerations.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art.
All of the factors have been considered with regard to the claims, with the most relevant factors discussed below.
The claimed formula contains large number of variable groups layered with substituents layered on substituents encompassing wide variety and number of conceivable structures that find little support in the specification. These substituents and hence the compounds of given formula are drawn to species that vary widely in physical and chemical properties such as size, molecular weight, stereochemistry, logP, acidity, basicity, etc. These factors are known in the art (see multiple references cited below) to greatly influence biological properties, for example, binding interaction between target protein and small molecule and art recognized concepts relating to productive small molecule-macromolecule interaction.
Enablement is acknowledged for one compound, that is compound of claim 12. But this compound is not even part of the rest of the subject matter and not relevant to the issue at hand. See rejection under 112-2 in this regard.
However that use of thiol starting material reacting with aldehyde to make ketal is not novel, the issue here is the plethora of possible thiol conceivable for the thiol part and aldehyde part to make thio acetal prodrugs. The large number of possibilities for variables for the formula finds no support in the specification. There are two issues. One is that there is no disclosure as to what makes the compounds prodrugs. What compounds (drugs) these convert to or revert to, in vivo, to regard the claimed compounds as prodrugs is not taught in the specification.
As to the ‘use’ prong of the enablement requirement, It is unclear if ROS activation is needed for all the compounds (to split into thiol compound and a carbonyl compound) to arrive at useful drug. It is noted that biological properties are unpredictable and are ultimately tide to the chemical structure. See “Role of the Development Scientist in Compound Lead Selection and Optimization” by Venkatesh, J. Pharm. Sci. 89, 145-154 (2000) (p. 146, left column). Likewise, J. G. Cannon, Chapter Nineteen in Burger's Medicinal Chemistry and Drug Discovery, Fifth Edition, Volume I: Principles and Practice, Wiley-Interscience 1995, pp. 783-802, teaches many caveats in analog design such as the following at page 799 column B:
Alteration of distances between portions of the pharmacophore of a molecule (or even' between other portions). may produce profound qualitative and/or quantitative changes in pharmacological actions.
Note that in University of Rochester v. G.D. Searle & Co., 68 USPQ2d 1424 at 1438, the screening for over 600 compounds was deemed to be undue. Applicant’s scope far exceeds this number. The specification must teach how to make and use the invention, not teach how to figure out for oneself how to make and use the invention. In re Gardner, 166 USPQ 138 (CCPA 1970). Therefore, one skilled in the art could not make or use the claimed invention without undue experimentation.
There is no structural guidance such as pharmacophore definition disclosed in the specification to guide one of skill in the art to choose from the plethora possibilities recited for the variables.
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Finding a prodrug is an empirical exercise. Predicting that in fact a prodrug that produces the active compound metabolically, in man, at a therapeutic concentration and at a useful rate is filled with experimental uncertainty. Although attempts have been made to predict drug metabolism de novo, this is still an experimental science. For a compound to be a prodrug, it must meet three tests. It must itself be biologically inactive. It must be metabolized to a second substance in a human at a rate and to an extent to produce that second substance at a physiologically meaningful concentration. Thirdly, that second substance must be biologically active. Determining whether a particular compound meets these three criteria in a clinical trial setting requires a large degree of experimentation. b) The direction concerning the prodrugs is limited to disclosure of generic concepts known to one of skill in the art at bottom of page 9. c) There is no working example of a prodrug of the compound of formula A. The derivatization of the only functional group available for any derivatization in the compound A is the carboxylic acid (to make a prodrug) finds no support in the specification with working examples for making and using, (especially in the context of the dose limitations in the claims).
d) The nature of the invention is clinical use of compounds and the pharmacokinetic behavior of substances in the human body. e) The state of the prodrug art, is summarized by Wolff, Burger's medicinal Chemistry and Drug Discovery, Vol.1, Principles and Practice, John Wiley & sons, New York, 1997. The table on the left side of page 976 outlines the research program to be undertaken to find a prodrug. The second paragraph in section 10 and the paragraph spanning pages 976-977 indicate the low expectation of success. In that paragraph the difficulties of extrapolating between species are further developed. Since, the prodrug concept is a pharmacokinetic issue, the lack of any standard pharmacokinetic protocol discussed in the last sentence of this paragraph is particularly relevant. f). Wolff (Medicinal Chemistry) in the last paragraph on page 975 describes the artisans making Applicants' prodrugs as a collaborative team of synthetic pharmaceutical chemists and metabolism experts. All would have a Ph.D. degree and several years of industrial experience. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved", and physiological activity is generally considered to be an unpredictable factor.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chemical Abstract Service. The blue colored numbers correspond to CAS Registry number.
For correlation of
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part of claim compare dependent claim 12 structure.
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L1=L2=’alkyl’ ; X’1=X’2=H
Here the term ‘alkyl’ is interpreted as (the intended) ‘alkylene’.
See rejection under Claim Rejections - 35 USC § 112-2.
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Any inquiry concerning this communication or earlier communications from the examiner should be directed to NIZAL S CHANDRAKUMAR whose telephone number is (571)272-6202. The examiner can normally be reached M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Andrew Kosar can be reached at (571) 272-0913. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/NIZAL S CHANDRAKUMAR/Primary Examiner, Art Unit 1625
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