DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Election/Restrictions
Applicants’ election without traverse of Invention I, corresponding to claims 1-5, 8-10, 14, 15, 23, 26, 28, 45, 57-59 and 62 in the reply filed on 3/16/26 is acknowledged.
Claims 7 and 60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, based on claim 7 being directed to a synthetic oligomer rather than the elected method, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/16/26.
Applicants’ election without traverse of the following species in the reply filed on 3/16/26 is acknowledged:
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Claims 28, 45, 57, 59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/16/26.
The elected peptoid synthetic oligomer species, evaluated as having androgen receptor antagonism per the specification and in the parent application falling within the scope of its allowed “antagonist of an androgen receptor” claims, is examined herein as related to the claimed methods.
Claim Status
Claims 1-5, 7-10, 14, 15, 23, 26, 28, 45, 57-60, 62 are pending.
Claims 6, 11-13,16-22, 24, 25, 27,29-44, 46-56, 61, 63-66 are cancelled.
Claims 7 and 60 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Invention, based on claim 7 being directed to a synthetic oligomer rather than the elected method, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/16/26.
Claims 28, 45, 57, 59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/16/26.
Claims 1-5, 8-10, 14, 15, 23, 26, 58 and 62 are pending and under examination.
Claims 1-5, 8-10, 14, 15, 23, 26, 58 and 62 are rejected.
Claims 1 and 62 are objected to.
Priority
The instant application, filed 09/20/2023 is a Continuation of 15938418, filed 03/28/2018, now U.S. Patent # 11766480 and having 3 RCE-type filing therein
15938418 is a Continuation of 14394996, filed 10/16/2014, now abandoned
14394996 is a National Stage entry of PCT/US2013/036719, International Filing Date: 04/16/2013
PCT/US2013/036719 Claims Priority from Provisional Application 61624865, filed 04/16/2012.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 4/7/26 Information Disclosure Statements (two separate filings) and provides a signed and dated copy of each herewith.
Drawings
The drawings are objected to because Figures 10A and 14 are unreadable given the small scripts. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities: On page 74, in paragraph 292, the inclusion of “22” in two places following a period should be clarified or these “22”s removed.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: Before “androgen receptor modulator moiety” at the bottom of page 2 of the claims, “a” should be replaced by “an”. Appropriate correction is required.
Claim 62 is objected to because it depends from a withdrawn claim. This can be overcome by amending claim 62 to be independent from claim 7 but include all structural limitations of claim 7.
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 9 and 10 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 pre-AIA the applicant regards as the invention.
Each of claims 9 and 10 includes the term “alkylene” for L1 and L2 of the androgen receptor modulator moiety. “Alkylene” is not defined in the specification, and based upon the structures in the specification, it appears that “alkylene” is synonymous with alkyl. However, an obsolete definition, see for instance https://en.wiktionary.org/wiki/alkylene, is that this is an alkene, which is an unsaturated, aliphatic hydrocarbon with one or more carbon–carbon double bonds. It is unclear which definition applies, and if the latter one, requiring one or more carbon-carbon double bonds is the definition, it is unclear why all examples do not have this. If the former definition, equivalence to alkyl, were to hold, it is unclear why a different term has been used. In summary, one of ordinary skill in the art cannot reasonably determine the metes and bounds of what is claimed given the lack of clarity of meaning of “alkylene”.
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 1-5, 8-10, 14, 15, 23, 26, 58 and 62 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.
This rejection pertains both to the peptoid synthetic oligomer elected species apart from treating or ameliorating prostate cancer when administered, and also expands beyond such species for the sake of compact prosecution.
Claim 1 is extremely broad with regard to:
Variations in structure of the peptoid synthetic oligomers, these extending from 2 to 45 overall monomers, of which 1 to 40 can comprise (as best understood) an androgen receptor modulator moiety, this in claim 1 having no given structure, and each R1 that is not (or does not comprise) an androgen receptor modulator moiety can have a very broad range of structures, with each R2 more limited;
The range of medical conditions “associated with androgen receptor”’ – which per claim 2 includes oncological and immune disorders, and per claim 5 extends to a wide range of divergent conditions.
The metabolic and/or physiological and/or other mechanisms that result from administering, to achieve PREVENTING, treating or ameliorating for the range of medical conditions “associated with androgen receptor”.
Claims depending from claim 1 retain substantial breadth as to one or more of the above.
The claimed subject matter is not supported by an adequate written description. There are insufficient guidance, structure/function relationships such as correlations between a particular structure and a function, and/or other relevant disclosure, nor examples that are representative of the diversity of the genera encompassed by the breadth of claim 1, as well as claims 2-5, 8-10, 14, 15, 23, 26, 58 depending from claim 1, given the broad range of structures, their possible effects of “androgen receptor modulator moiety” on androgen receptors – NOTE that this includes indirect effects, such as affecting a pathway that affects indirectly an androgen receptor, and also NOTE that this includes combined, cumulative effects of a multiple of R1 moieties, each contributing to an overall chemical binding that may affect, such as by binding directly to or nearby a single (or multiple) androgen receptor, and including even assuming that the androgen receptor modulator moiety falls with a recognized class of androgens or structurally similar molecules, whether such is/are functioning as agonist(s) or antagonist(s), and such effect on a wide and diverse range of medical conditions “associated with androgen receptor”, and also including how an administering such as a single administering results in preventing for the diverse range of medical conditions “associated with androgen receptor” (i.e., preventing, when there is no reasonable technical basis to consider that a single, or several, administerings in a mammal would prevent any of the diverse range of medical conditions “associated with androgen receptor” from ever occurring years later – there is no evidence or technical basis that would support the administering of the peptoid synthetic oligomers function analogously to a vaccine).
Nothing with regard to support in the application as filed, no guidance, no structure/function relationships, insufficient examples, reasonably leads to a conclusion of possession for what is claimed in claim 1 nor in claimed depending from claim 1. Of the several oligomers evaluated, 1-7, the specification, para 268, states that “Although oligomers 3-7 suppress the proliferation of LNCCaP-abl cells, they do so through different mechanisms, given the distinctive profiles for competitive binding elicited by the oligomers.” There is no guidance regarding how to predict any of various different mechanisms for larger, longer, or different peptoid synthetic oligomers encompassed by the claims, which include very broad genera, nor how to select from such genera oligomers that possess agonistic behavior with an androgen receptor, so as to be able to utilize such oligomers for preventing, treating or ameliorating conditions associated with androgen receptor where agonism would be beneficial. This clearly goes to a lack of possession of the claimed genera based on possession and description of a small number of species that are not commensurate in scope with what is claimed. Related issues are discussed further below.
The skilled artisan cannot envision the detailed chemical structure alternatives of the peptoid synthetic oligomers across the range of such structures, which have the respective required activity/function without further testing, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention. The compound itself is required; in this case at least a sufficient number of species that are representative of the diversity of each respective genus, and/or a disclosure of what is critical as far as sequence(s) and what does not work to achieve a particular claimed activity/function, here for the instant methods to achieve preventing, treating or ameliorating any of the medical conditions within the range of medical conditions “associated with androgen receptor”. Here, given the breadth of possible modifications of the structure of the peptoid synthetic oligomers, this including differences in structure and spacing of the 1-40 androgen receptor modulator moieties (which per above as noted include multiple collective interactions for function), with interspersed R1 structures that themselves are highly diverse (but presumably not ‘qualifying’ as androgen receptor modulator moieties) – where only several shorter structures were constructed and identified to possess antagonist properties against an androgen receptor in limited evaluations (and a few other peptoid synthetic oligomers apparently did not bind well, see specification pages 64-74, including that oligomers 1-3 and 7 “do not compete against DHT for binding at concentrations up to 10 uM” – this apparently with LNCaP cells, but when evaluated in LNCaP-abl cells oligomer 3 was suggested to be “likely functioning as an AR antagonist”, on page 65 summarizing “Although oligomers 3-7 suppress the proliferation of LNCaP-abl cells, they do so thorough different mechanisms” (in later paragraphs focusing on oligomers 6 and 7)), given the possible variations in structure, the acknowledged different effects on valence and spacing - see para 266, albeit such statement about increasing is stated to be based on reference 30, however it appears that this is an error and should properly refer to reference 29, which is Holub et al., Peptoids on Steroids: Precise Multivalent Estradiol-Peptidomimetic Conjugates Generated via Azide-Alkyne [3+2] Cycloaddition Reactions, QSAR & Comb. Sci. 26, 2007, No. 11-12, 1175-1180, applied below, which provides a limited range of such valences and spacings, see its Table 2, also noting that this demonstrates binding to the estrogen receptor (neither demonstrating, apparently, a distinction between agonism and antagonism), this limited range of valency and spacing, see Holub Figure 1, showing at most two non-receptor moieties between receptor moieties, and at most six receptor moieties, not commensurate in scope with what is instantly claimed), and of particular relevance applicant’s own oligomer examples also are highly limited, see specification pages 60-63, such structures not representative of the claimed genus of peptoid synthetic oligomers, the skilled artisan is left to determine what range of variations can still provide some level of relevant biological activity to prevent, treat, or ameliorate any of the wide and diverse range of claimed medical conditions “associated with androgen receptor” (please see claim 5 for a non-limiting example of what this encompasses per the applicant’s claiming).
Further regarding of the wide and diverse range of claimed medical conditions “associated with androgen receptor”, at least given claim 5’s inclusion of “reduction in libido and sexual dysfunction,” for male mammals this would reasonably appear to call for administering an agonist of androgen receptor, to increase testosterone output. Yet the application focuses on the findings regarding the most evaluated peptoid synthetic oligomers that these function on antagonists (for a limited type of prostate cancer cells). There is insufficient guidance as to how to design and structure the peptoid synthetic oligomers from the claimed genus of any of the claims under examination to achieve the claimed therapeutic outcomes – preventing, treating or ameliorating, for “reduction in libido and sexual dysfunction” or any of the other of the wide and diverse range of conditions listed in claim 5, let alone other medical conditions that may be considered “associated with androgen receptor.” Regarding the peptoid synthetic oligomer elected species, there is no reasonable basis for possession of the method for preventing, treating or ameliorating “reduction in libido and sexual dysfunction” when such species has been demonstrated to be an antagonist of androgen receptor, at least given that an agonist of such receptor would reasonably be required to increase testosterone production in a subject in need thereof.
Regarding colon cancer, Gillesson et al. JNCI, Vol. 102, Issue 23, December 1, 2010, pp 1760-1770, teaches and concludes that long term androgen deprivation for prostate cancer (which would reasonably be achieved when administering one of applicant’s antagonists to androgen receptor) “Is associated with an increased risk of colorectal cancer,” page 1760. Applicant has neither articulated, taught, explained nor provided a reasonable technical basis nor any structure/function relationship, to educate one or ordinary skill in the art nor demonstrate which among its claimed to be administered peptoid synthetic oligomers would function to prevent, treat or ameliorate colon cancer given that most of its few examples were stated to be antagonists of the androgen receptor in limited prostate cancer cell types. The latter “most of its few examples” includes the peptoid synthetic oligomer elected species.
Regarding a medical conditions “associated with androgen receptor” that is not listed in the claims, Rosario and Pike, Brain Res Rev. 2008 March ; 57(2): 444–453, teach that “Testosterone depletion leads to functional impairments and increased risk of disease in androgen-responsive tissues throughout the body, including brain. … Emerging data suggest that the regulatory actions of androgens on both Aβ and the development of AD support consideration of androgen therapy for the prevention and treatment of AD [Alzheimer’s Disease],” Abstract. There are no known therapeutic methods to prevent Alzheimer’s Disease, yet applicant is so claiming to have achieved this, and alternatively to treat or ameliorate AD, yet the focus of what applicant has evaluated is on antagonists of androgen receptor. Applicant has neither articulated nor provided a reasonable technical basis nor any structure/function relationship, to educate one or ordinary skill in the art nor demonstrate which among its claimed to be administered peptoid synthetic oligomers would function to prevent, treat or ameliorate Alzheimer’s Disease given that most of its few examples were stated to be antagonists of the androgen receptor in limited prostate cancer cell types. The latter “most of its few examples” includes the peptoid synthetic oligomer elected species.
Applicant is leaving completion of the invention (if possible for what is claimed) to someone else. See also Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
This rejection applies to the elected species structure in that it is not considered to be able to prevent, treat or ameliorate the diverse range of conditions encompassed by the claims, and at least for preventing, there is no possession when considering prostate cancer.
The full breadth of the claims, including for each of the dependent claims under examination, does not meet the written description provision of 35 U.S.C. §112, first paragraph. Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-5, 8-10, 14, 15, 23, 26, 58 and 62 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or ameliorating prostate cancer with several specific antagonists of androgen receptor, does not reasonably provide enablement for the scope of what is claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
This rejection extends beyond the elected species for treatment of prostate cancer, including addressing the lack of enablement for the elected species peptoid synthetic oligomer to prevent, treat or ameliorate medical conditions associated with androgen receptor that are not prostate cancer and would benefit from agonism at the androgen receptor rather than antagonism.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required (also recited in MPEP 2164.01(a)): (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
The analysis is as follows:
The breadth of the claims:
Claim 1 is extremely broad with regard to:
a) Variations in structure of the peptoid synthetic oligomers, these extending from 2 to 45 overall monomers, of which 1 to 40 can comprise (as best understood) an androgen receptor modulator moiety, this in claim 1 having no given structure, and each R1 that is not (or does not comprise) an androgen receptor modulator moiety can have a very broad range of structures, with each R2 more limited;
b) The range of medical conditions “associated with androgen receptor”’ – which per claim 2 includes oncological and immune disorders, and per claim 5 extends to a wide range of divergent conditions.
c) The metabolic and/or physiological and/or other mechanisms that result from administering, to achieve PREVENTING, treating or ameliorating for the range of medical conditions “associated with androgen receptor”.
Claims depending from claim 1 retain substantial breadth as to one or more of the above.
(B) The nature of the invention: therapeutic, medical, and including preventing a wide range of diverse medical condition that applicant has joined by “associated with androgen receptor”, however such medical conditions differ in their need for increased or decreased androgens.
(C) The state of the prior art: forming peptoid synthetic oligomers was known in the art, for example see Holub et al., Peptoids on Steroids: Precise Multivalent Estradiol-Peptidomimetic Conjugates Generated via Azide-Alkyne [3+2] Cycloaddition Reactions, QSAR & Comb. Sci. 26, 2007, No. 11-12, 1175-1180, and of Holub et al., Mol. BioSyst., 2011, 7, 337–345, both cited in 4/7/26 IDS so not supplied herewith.
Gillesson et al. JNCI, Vol. 102, Issue 23, December 1, 2010, pp 1760-1770, teaches and concludes that long term androgen deprivation for prostate cancer (which would reasonably be achieved when administering one of applicant’s antagonists to androgen receptor) “Is associated with an increased risk of colorectal cancer,” page 1760. Applicant has neither articulated, taught, explained nor provided a reasonable technical basis nor any structure/function relationship, to educate one or ordinary skill in the art nor demonstrate which among its claimed to be administered peptoid synthetic oligomers would function to prevent, treat or ameliorate colon cancer given that most of its few examples were stated to be antagonists of the androgen receptor in limited prostate cancer cell types. This conundrum increases the amount of experimentation that is required.
Regarding a medical condition “associated with androgen receptor” that is not listed in the claims, Rosario and Pike, Brain Res Rev. 2008 March; 57(2): 444–453, teach that “Testosterone depletion leads to functional impairments and increased risk of disease in androgen-responsive tissues throughout the body, including brain. … Emerging data suggest that the regulatory actions of androgens on both Aβ and the development of AD support consideration of androgen therapy for the prevention and treatment of AD [Alzheimer’s Disease],” Abstract. There are no known therapeutic methods to prevent Alzheimer’s Disease, yet applicant is so claiming to have achieved this, and alternatively to treat or ameliorate AD, yet the focus of what applicant has evaluated is on antagonists of androgen receptor. Applicant has neither articulated nor provided a reasonable technical basis nor any structure/function relationship, to educate one or ordinary skill in the art nor demonstrate which among its claimed to be administered peptoid synthetic oligomers would function to prevent, treat or ameliorate Alzheimer’s Disease given that most of its few examples were stated to be antagonists of the androgen receptor in limited prostate cancer cell types. Given the difficulty of preventing, treating or ameliorating Alzheimer’s Disease, the amount of experimentation that is required is extremely high.
(D) The level of one of ordinary skill: The level of ordinary skill in the art is high.
(E) The level of predictability in the art: low, with regard to how a different structure of a peptoid synthetic oligomer across the range of sizes and structures and types of spaced apart androgen receptor modulator moieties would affect a mammal having any of the wide and diverse range of medical conditions associated with androgen receptor.
(F) The amount of direction provided by the inventor: very limited with regard to what structures provide for the claimed preventing, treating or ameliorating the range of medical conditions associated with androgen receptor. Of the several oligomers evaluated, 1-7, which includes the elected species, compound 6, the specification, para 268, states that “Although oligomers 3-7 suppress the proliferation of LNCCaP-abl cells, they do so through different mechanisms, given the distinctive profiles for competitive binding elicited by the oligomers.” There is no guidance regarding how to predict any of various different mechanisms for larger, longer, or different peptoid synthetic oligomers encompassed by the claims, which include very broad genera, nor how to select from such genera oligomers that possess agonistic behavior with an androgen receptor, so as to be able to utilize such oligomers for preventing, treating or ameliorating conditions associated with androgen receptor where agonism would be beneficial. This clearly goes to a lack of guidance as to what features are required to achieve the preventing, treating or amelioration across the ranges of what is claimed, this including for the elected species for conditions associated with androgen receptor where agonism rather than antagonism would be therapeutic.
(G) The existence of working examples: very limited, focusing on the effects of a small number of peptoid synthetic oligomers effects on two prostate cancer cell types. Most of those evaluated were stated to be antagonists of androgen receptor having different mechanisms (see above), but how to expand from this to what is claimed was not articulated or demonstrated, nor is there a reasonable technical basis to expand from these structures and their results with these two cell types to the scope of what is claimed with regard to what medical conditions can reasonably be treated.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. The skilled practitioner would first turn to the instant description for guidance in using the claimed invention. However, the description lacks clear evidence, technical reasoning or other support that Applicant has demonstrated how to practice the claimed method across the combination of peptoid synthetic oligomers and medical conditions associated with androgen receptors, to achieve one or more of the claimed preventing, treating or ameliorating. As such, the skilled practitioner would turn to the prior art for such guidance, however the prior art does not discuss to any meaningful extent how to use the claimed compounds to achieve what is claimed. Finally, said practitioner would turn to trial and error experimentation to determine how, and whether it is possible, to prevent, treat or ameliorate the wide and diverse range of medical conditions “associated with androgen receptor” (including the more limited types/lists in claims 2-5) with any one or more of the broad genus of peptoid synthetic oligomers encompassed by any of the claims, especially given the number of variables as to spacing, numbers and types of androgen receptors, and combinations resulting from consideration of overall length of the peptoid synthetic oligomers and ranges and types of R1s that are not androgen receptor modulator moieties. Such clearly amounts to undue experimentation.
MPEP 2164.01(a) states, “A conclusion of lack 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. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claims 1-5, 8-10, 14, 15, 23, 26, 58 and 62 accordingly are rejected as not being enabled commensurate with the scope of what is claimed. The dependent claims, although limiting one or more variables to a degree, nonetheless still retain enormous breadth given the scopes of the other variables set forth above, and the resultant undue experimentation to enable this smaller but still very large scope of variable combinations.
Claim Rejections – 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102€, (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
1. Claims 1-5, 8-10, 14, 15, 23, 26 and 62 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Holub et al., Peptoids on Steroids: Precise Multivalent Estradiol-Peptidomimetic Conjugates Generated via Azide-Alkyne [3+2] Cycloaddition Reactions, QSAR Comb. Sci. 26, 2007, No. 11-12, 1175-1180 (Holub), cited in 4/7/26 IDS, in view of Ockrim et al., J Urol. 2003 May;169(5):1735-7 (Ockrim), as evidenced by Nakhla et al., THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 272, No. 11, Issue of March 14, pp. 6838–6841, 1997 (Nakhla).
This rejection expands beyond the elected peptoid synthetic oligomer species treating prostate cancer.
Claim 1 is directed to a method which comprises administering to a mammal a synthetic oligomer according to formula Ia or Ib, set forth therein, “provided that at least one monomer or up to 40 monomers comprises a [sic] androgen receptor modulator moiety,” the method per the preamble “for preventing, treating or ameliorating in a mammal a medical condition,” the last lines of the claim stating that the medical condition “is associated with androgen receptor.” No structural limits are provided for the androgen receptor modulator moiety moieties.
Holub teaches multiple species, and a general synthetic approach, for peptoid polymers comprising peptidomimetic conjugates, most of these having multiple steroid moieties attached to a peptidomimetic chain at spaced intervals, see Fig. 1, Fig. 2, and method section.
Holub, legend of Figure 1, identifies its compounds 1-4 as estradiol peptidomimetic conjugates, and provides in Table 2 EC50 results based on competitive binding to the estrogen receptor, and in the Abstract states that avidities of these compounds to the estrogen receptor are enhanced when the valency of hormone ligand presentation is increased.
Holub, legend of Figure 2, identifies the compounds therein, numbered 5-7, as “Ethisterone -peptidomimetic conjugates showing precise multivalent display of progesterone receptor ligands.”
These compounds were stated to be produced by a synthetic reaction to join ethisterone to the peptidomimetic chain.
After the synthetic reaction to ligate the steroid moiety or moieties to the triazole(s) the ethisterone has been modified to (or is erroneously depicted as) testosterone, this based on the following:
Ethisterone structure from https://pubchem.ncbi.nlm.nih.gov/compound/ethisterone#section=2D-Structure:
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205
300
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Compound 5 from Fig. 2 of Holub (ignore upper right partial compound):
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371
349
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The steroid of compound 5 lacks the C triple bond C shown in Fig. 5, this forming the azole ring during reaction. Please note that compounds 6 and 7 of Fig. 2 also depict testosterone moieties along the peptoid chain, notwithstanding the legend of the figure.
The steroid of compounds 5-7 based on the Examiner’s comparisons is testosterone (image copied from https://en.wikipedia.org/wiki/Testosterone), however in compound 5 bonded to the triazole from the carbon having the -OH in the image below):
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Elsewhere as noted Holub depicts ethisterone also joined to peptoid chains, see Figure 1, and focuses its studies on the effectiveness to bind to estrogen receptor.
Holub does not explicitly teach its peptoids that comprise ethisterone or testosterone to be administered to a mammal “for preventing, treating or ameliorating in a mammal a medical condition” that “is associated with androgen receptor.”
The level of ordinary skill in the art is high.
As evidenced in Nakhla “Estradiol Activates the Prostate Androgen Receptor and Prostate specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin,” Title, see also Abstract, so establishing that estradiol, at least under conditions, modulates by activating the prostate androgen receptor, so is an androgen receptor modulator moiety.
After teaching that parenteral estrogens prevent first pass hepatic metabolism and substantially reduce cardiovascular risk (as opposed to oral estrogens), Ockrim teaches that transdermal estradiol produced an effective response in patients with advanced prostate cancer, these patients achieved castrate levels of testosterone within 3 weeks, and as noted in Results functional and symptomatic quality of life domains improved except for mild or moderate gynecomastia occurred in 80% of patients. Thus, Ockrim teaches treating prostate cancer medical condition, which is associated with an androgen receptor, by administering estradiol transdermally.
It is evident from Nakhla that estradiol activates the prostate androgen receptor, so is an androgen receptor modulator and per Ockrim can be used to treat prostate cancer, and is favored over use of luteinizing hormone releasing hormone agonists (see Ockrim pages 1735-37). Based on Holub’s improved results with multiple active moieties along the peptoid chain, one of ordinary skill in the art would have been motivated to improve the effectiveness of estradiol, as taught in Ockrim, to modulate an androgen receptor, including to treat a medical condition associated with androgen receptor, including prostate cancer, by providing one or more estradiol monomers on a peptoid chain as clearly taught in Holub. There would have been a reasonable expectation of success in treating prostate cancer via such modulation of androgen receptors given the teachings and results of the references.
Accordingly, claim 1 would have been obvious.
Also obvious on the same basis are claims 2-5, which include treating a cancer and specifically prostate cancer in claim 4, and treating androgen receptor dependent prostate cancer in claim 5, this rejection again based on the teachings of the references (with estradiol being compared to and found superior to luteinizing hormone releasing hormone agonists).
Because the compounds of Holub comprise at least one triazoyl moiety, see Figure 1, claim 8 would have been obvious.
Because the estradiol monomers of Holub Figure 1 are encompassed by the first AR in claim 9:
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and otherwise meets claim 9’s formula II, claim 9 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of Holub Figure 1 are encompassed, as best understood, by the first AR in claim 10, claim 10 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of Holub Figure 1 are encompassed, as best understood, by the first AR in claim 14 (Iva), claim 14 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of Holub Figure 1 are encompassed, as best understood, by the first AR in claim 15 (Va), claim 15 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of Holub Figure 1 are encompassed, as best understood, by the first AR in claim 23 (Iva’), claim 23 would have been obvious on the same bases applied to claim 1.
Claim 26 also would have been obvious based on the teachings of the references on the same bases applied to claim 1, the examiner noting at to the claim 26 formula VIII that each R1 encompasses an androgen receptor modulator moiety, such as those set forth in the references (claim 26 further limits claim 1 by requiring certain spacing of particular structures of androgen receptor modulator moieties, but does not exclude these from the R1s, and for example compound 3 the structures of Holub is met in claim 26 when p=3, the leftmost R1 is ethisterone, the next two R1s are CH2OCH3, the leftmost R3 also is ethisterone, u=2 and each such R1 is CH2OCH3, y=1, q=2, and each such R1 is CH2OCH3).
Claim 62 is broadly directed to modulating androgen receptor activity in a human cancer cell in which said receptor is present, comprising contacting the cell with an effective amount of an oligomer according to claim 7, which comprises similar limitations as instant claim 1 as to the synthetic oligomer, however adding the exclusion:
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Claim 62 would have been obvious based on the references applied to claim 1, wherein the administering is of compound 4 of Figure 1 of Holub:
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, which does not meet the noted exclusion of claim 7. There would have been a reasonable expectation of success based on the reasoning applied to claim 1, the examiner also noting the superior EC50 for this compound as set forth in Table 2 of Holub.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this 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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-5, 8-10, 14, 15, 23, 26 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 20 of U.S. Patent No. 8524663, in view of in view of Ockrim et al., J Urol. 2003 May;169(5):1735-7 (Ockrim), as evidenced by Nakhla et al., THE JOURNAL OF BIOLOGICAL CHEMISTRY, Vol. 272, No. 11, Issue of March 14, pp. 6838–6841, 1997 (Nakhla).
In Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 (Fed. Cir. 2010), the Court determined that claims of a later patent were held invalid for obviousness-type double patenting when the earlier patent claimed a compound and disclosed its utility in its specification, and later patent claimed a method of using the compound for a use described in the specification of the earlier patent.
Here, the last structure of claim 20 of the ‘663 sets forth multiples of iterative portions each comprising ethisterone as an androgen modulating moiety:
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(other previous species of claim 20 also comprise multiple ethisterone moieties separated by two “R1” type pendant groups from the peptoid backbone).
The ‘663 specification clearly teaches use of the oligomers to treat cancers such as prostate and breast cancers, paras 12, 140.
To the extent that a cancer such as prostate cancer is treated by the ‘663 claim 20 oligomers, the following is applied. The level of ordinary skill in the art is high.
As evidenced in Nakhla “Estradiol Activates the Prostate Androgen Receptor and Prostate specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin,” Title, see also Abstract, so establishing that estradiol, at least under particular conditions, modulates by activating the prostate androgen receptor, so is an androgen receptor modulator moiety.
After teaching that parenteral estrogens prevent first pass hepatic metabolism and substantially reduce cardiovascular risk (as opposed to oral estrogens), Ockrim teaches that transdermal estradiol produced an effective response in patients with advanced prostate cancer, these patients achieved castrate levels of testosterone within 3 weeks, and as noted in Results functional and symptomatic quality of life domains improved except for mild or moderate gynecomastia occurred in 80% of patients. Thus, Ockrim teaches treating prostate cancer medical condition, which is associated with an androgen receptor, by administering estradiol transdermally.
It is evident from Nakhla that estradiol activates the prostate androgen receptor, so is an androgen receptor modulator and per Ockrim can be used to treat prostate cancer, and is favored over use of luteinizing hormone releasing hormone agonists (see Ockrim pages 1735-37). Based on Ockrim and the teaching of treating breast and prostate cancer in the ‘663, one of ordinary skill in the art would have been motivated to improve the effectiveness of estradiol, as taught in Ockrim, to modulate an androgen receptor, including to treat a medical condition associated with androgen receptor, including prostate cancer, by providing one or more estradiol monomers on a peptoid chain as clearly taught in claim 20 of the ‘663. There would have been a reasonable expectation of success in treating prostate cancer via such modulation of androgen receptors given the teachings and results of the references.
Accordingly, claim 1 would have been obvious.
Also obvious on the same basis are claims 2-5, which include treating a cancer and specifically prostate cancer in claim 4, and treating androgen receptor dependent prostate cancer in claim 5, this rejection again based on the teachings of the references (with estradiol being compared to and found superior to luteinizing hormone releasing hormone agonists).
Because the compounds of the ‘663 claim 20 comprise at least one triazoyl moiety, see Figure 1, claim 8 would have been obvious.
Because the estradiol monomers of the ‘663 claim 20 are encompassed by the first AR in claim 9 and otherwise meets claim 9’s formula II, claim 9 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of the ‘663 claim 20 are encompassed, as best understood, by the first AR in claim 10, claim 10 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of the ‘663 claim 20 are encompassed, as best understood, by the first AR in claim 14 (Iva), claim 14 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of the ‘663 claim 20 are encompassed, as best understood, by the first AR in claim 15 (Va), claim 15 would have been obvious on the same bases applied to claim 1.
Because the estradiol monomers of Holub Figure 1 are encompassed, as best understood, by the first AR in claim 23 (Iva’), claim 23 would have been obvious on the same bases applied to claim 1.
Claim 26 also would have been obvious based on the teachings of the references on the same bases applied to claim 1, the examiner noting at to the claim 26 formula VIII that each R1 encompasses an androgen receptor modulator moiety, such as those set forth in the references (claim 26 further limits claim 1 by requiring certain spacing of particular structures of androgen receptor modulator moieties, but does not exclude these from the R1s, and for example when n=3 that oligomer of ‘663 claim 20 structures is met in claim 26 when p=3, the leftmost R1 is ethisterone, the next two R1s are CH2OCH3, the leftmost R3 also is ethisterone, u=2 and each such R1 is CH2OCH3, y=1, q=2, and each such R1 is CH2OCH3).
Claim 62 is broadly directed to modulating androgen receptor activity in a human cancer cell in which said receptor is present, comprising contacting the cell with an effective amount of an oligomer according to claim 7, which comprises similar limitations as instant claim 1 as to the synthetic oligomer, however adding the exclusion:
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Claim 62 would have been obvious and is rejected under this section based on the references applied to claim 1, given that what is set forth in the last noted portion of claim 20 of the ’663 comprises ethisterone and not testosterone.
Claims 1-5, 8-10, 14, 15, 23, 26, 58 and 62 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 9, 14, 16 and 17 of U.S. Patent No. 11766480. Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘480 claims are directed to antagonists of an androgen receptor, including in claims 14 and 15 methods for inhibiting androgen receptor activity in a cancer cell, so would treat a cancer such as prostate cancer where such would be therapeutic, and such ‘480 methods using such antagonists are encompassed by the instant claims that more broadly are directed to modulating (at least per instant claim 1 where 1-40 monomers comprise a [sic] androgen receptor modulator moiety, these comprising the same structures as the ‘480).
Instant claims 1-5, 8 and 62 would have been obvious over the ‘480 claims 1 and 14.
Instant claims 9, 10, as best understood, and claims 14 and 15, would have been obvious over the ‘480 claims 1, 4 and 14.
Instant claim 23 would have been obvious over the ‘480 claims 1, 14 and 16.
Instant claim 26 would have been obvious over the ‘480 claims 1, 14 and 17.
Instant claim 58 would have been obvious over the ‘480 claims 1, 9 and 14.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925, and whose direct facsimile number is (571)270-8925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
Prosecution Insights