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 .
Claims 1, 69-87 are before the Examiner.
Claim Rejections – Improper Markush Group
The nonstatutory Markush grouping rejection is based on a judicially approved “improper Markush grouping” doctrine. Claims 1, 69-87 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, formulae III-2 and III-4 of base claims 1 and 69 as well as of independent claim 85. The only at once recognizable invariable part of these formulae form only a small portion of the ring systems. Further the L1 part of III-2 contain rings (4-12 membered) that just are vastly different from the fused-piperazine of III-4. The Examiner has to consider whether
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(also see species claim 85) have similar physical, chemical and biological (DGK inhibiting) properties. The claim 85 also includes compounds that are outside the ring systems of III-2 and III-4, such as
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. In addition, the compounds include many known and unknown structural motifs. That L1 could be a 12 membered ring with 4 consecutive heteroatoms, defies commonsense organic and medicinal chemistry principles. 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 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, 69-87 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making some possibilities of the claimed formulae III-2 and III-4, does not reasonably provide enablement for plethora of conceivable compounds of these formulae. For example, it is not seen where in the specification enabling disclosure compounds with combination having X, Y and U are C based or X, Y and U are all N . Also see sections under Claim Rejections – Improper Markush Group. 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 formulae are drawn to bicyclic (Formula III-2), tetracyclic (Formula III-4) and bicyclic (claim 85) ring fused compounds. Depending on the fusion and the variables within the ring systems X, Y, Z and U being N or C based there are large number conceivable ring systems crossing boundaries of patent classification systems. In addition these rings also have substituents layered on substituents encompassing wide variety and number of structures there is little support in the specification for making and using for the breadth of the claims. 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.
There is no guidance on what to choose from these large number of structural moieties defined with umbrella terms such as heteroarylene, or heterocyclyl or where and how to link these moieties with rest of the formulae.
Enablement is a two prong (make and use) requirement.
Consider for example Formula III-2. For the ring system itself, of the many combinations of X, Y and U recited, only one possibility of
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is found for enabling disclosure Even with this ring system, as to the substituents, there is no direction or guidance for making anything other than the possibility
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. There is no disclosure on how to make any of R2
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Specification is silent with respect to procuring starting materials that can be used in the chemistry scheme at page 151 enabling for
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to make any and all R2 recited.
According to the U.S. Court of Customs and Patent Appeals in In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 101, "[o]rdinarily no problem in this regard arises since the method of preparing almost all starting materials can be set forth in writing if the materials are not already known and available to the workers in the art, and when this is done the specification is enabling to the public". In re Argoudelis , De Boer, Eble, and Herr 168 USPQ 99 at 104, "it is essential that there be no question that, at the time an application for patent is filed, (emphasis in original) the invention claimed therein is fully capable of being reduced to practice (i.e., that no technological problems, the resolution of which would require more than ordinary skill and reasonable time, remain in order to obtain an operative, useful embodiment)." . Organic chemistry is unpredictable and capricious as taught by Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim pg. IX of Preface pg. 1-15 which teaches that ” …as will be shown throughout this book, the outcome of organic reactions is highly dependent on all structural features of a given starting material, and unexpected products may readily be formed. [8]……...Even the most experienced chemist will not be able to foresee all potential pitfalls of a synthesis, especially so if multifunctional, structurally complex intermediates must be prepared.…..”
This only an example for 112-1 enablement issues with respect to ‘how to make’ aspect.
Also consider the variables L1 of claim 1 formula. The notion the
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finds very little support, given that the only enabling disclosure for making the bond between the tricyclic system and L1 is made by the displacement halogen (addition elimination when X-=N). For L1, N-heterocycle with up to 4 heteroatoms in a 4-memebered ring or any rings with consecutive heteroatoms suggests impossible substituent possibilities such as
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. Such formulae for L1
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ring systems suggest ‘impossible substituent’ problems. 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. ... Alternatively, if it is impossible, then it is not correct.
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. It is not that some compounds do show acceptable activity to satisfy the 112-1, rather the issue is breadth of the claims. For example, the pictured compounds have many core structures (see rejection under improper Markush); further within these different core structures the substituents are limited with respect to working example, direction and guidance. As such what combination of template and variables (R groups) that would provide for predictable results is inconsistent for enabling disclosure. It is noted that the difference between DGK inhibiting compounds of W02021258010 IN Table 1 at page 26-56 for example compound 110 at bottom of page 53 is
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in the place of the substituent R30 which is not included in the instant claim formula III-2.
That is substituents do make patentable definition.
Pharmacological activity in general is a unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Disclosure in the specification with respect use aspect of 112-1 is found in Table 2, showing similar compounds showing different activity in DGKa and DGKz assays. There is no specific pharmacophore taught in the specification for predictable activity. Further note that the claims are drawn to different ring systems as discussed above.
In this case, according to Purow, Cancers (Basel). 2022 Mar 1;14(5):1269, DGKα Inhibition as a Promising Therapeutic Strategy and that DGKα inhibition thus offers the highly attractive potential: DGKα inhibition thus offers the highly attractive potential for multifaceted direct action against GBM with simultaneous immune-boosting activities and potential antiangiogenic activity as well (summarized in Figure 1). That being said, it is highly likely that truly effective therapy for GBM will likely require combinations, and this applies to DGKα inhibition as well despite its multiple mechanisms of action. DGKα inhibition may in fact lend itself to numerous synergistic combinations with other anti-cancer drugs, for GBM and other cancers as well. While we have focused here on GBM, there is every indication that DGKα inhibition will be applicable to other brain tumor types as well. Furthermore, many of the same points made here should also apply to cancers outside the CNS. Fulfilling the potential of DGKα inhibition for GBM and other cancers will likely require the development of new small-molecule inhibitors, but such work is underway and in the meantime there may be utility in a repurposed drug such as ritanserin. Similarly, according to Sakane (2021 Oct 16;13(20):5190), ‘DGKα acts as an antiapoptotic/ PR proliferation factor in cancer cells. In contrast, DGKα attenuates the functions of T cells. Therefore, DGKα-selective inhibitors are expected to be ideal anticancer medicines because the inhibition of DGKα suppresses cancer cell proliferation and simultaneously activates T cell function (Figure 3). Moreover, synergistic effects of DGKα inhibition and PD-1/PD-L1 blockade would provide a promising new strategy for refractory cancer therapy (Figure 3). Furthermore, it is possible that the inhibition of DGK synergistically enhances the effects of DGKα inhibition (Figure 3). Immediate development of genuine DGKα-specific inhibitors (and DGKζ-specific inhibitors) is needed”. Language such as ‘potential’ or ‘promising strategy’ are not tantamount to predictive results. Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent protection is granted in return.
There is a substantial gap between what is taught in the specification and what is being claimed. For these reasons, one skilled in the art would be faced with undue amount of research. The specification lacks disclosure sufficient to make and use the invention, in predictable manner, commensurate with the scope of the claims.
MPEP 2164.01(a) states, “A conclusion of Iack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. ln re Wright, 999 F.2d 1557,1562, 27 USPQ 2d 1510, 1513 (Fed. Cir. 1993).'' That conclusion is clearly justified here. Thus, undue experimentation would be required.
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, 69-87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 196-205 of copending Application No. 18852245 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims contain overlapping subject matter.
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of claim 196 and
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of claim 202 overlap with claim 1 and claim 79 of instant case. Claim 205 and instant claim 87 are drawn to same method.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 69-87are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12077538. Although the claims at issue are not identical, they are not patentably distinct from each other as explained below:
Compare instant claim
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overlaps with compound formula of claim 1 of 12077538:
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The difference is substituent in the T containing ring of 12077538 and further the difference is the
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(above pictured instant compound partial structure)
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(partial structure of 12077538). That C and N are interchangeably usable is not only consistent with definition of U and T in 12077538, further also as per the specific examples in species claim 85 of instant case and in the generic formulae of instant claims 1 and 69. The inherent biological property of the claimed compounds in both cases are the same, DGK inhibition.
Obviousness can be established by combining or modifying the teachings of the disclosures in both cases and corresponding claims, where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art.
Accordingly, the claims do not recite an unobvious distinction. Further, the teaching in 12077538 is relevant not only for what it expressly teaches, but also for what it would have conveyed to one of ordinary skill in the art. See In re Opprecht, 12 USPQ2d 1235, 1236 (Fed. Cir. 1989); In re Bode, 193 USPQ 12 (CCPA 1976). In light of the foregoing discussion, the Examiner finds that the claimed subject matter as a whole would have been obvious to one of ordinary skill in the art at the time the invention was made, in view of the cited references and the knowledge generally available in the art.
Likewise, (likewise means for the same above rationale) claims 1, 69-78, 79, 80-84, 85, 86, 87 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-44 of copending Application No. 18486374 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims contain overlapping subject matter.
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of claim 23 and of
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claim 34 overlap with claim 1 and claim 79 of instant case. Claim 44 and instant claim 87 are drawn to same method. Compare species claim 44 compounds of bottom of instant claim page 24
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Feldman, Understanding ‘Evergreening’ : Making Minor Modifications Of Existing
Medications To Extend Protections, Health Affairs June 2022 41:6, 801-804
Dwivedi, Evergreening: A deceptive device in patent rights, Technology in Society 32 (2010) 324–330.
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.
Claim 85 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.
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The above preamble is inconsistent MPEP guidelines that claim complete in itself. Depending on specification is relies on disclosure in the specification. A patent claim must be "complete in itself". While the claim must find clear support and antecedent basis in the specification, it cannot rely solely on the specification or external documents to fill in missing functional limitations. See MPEP 2173 Claims Must Particularly Point Out and Distinctly Claim the Invention [R-10.2019].
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.
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, 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
Prosecution Insights