DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. GB2019475.9, filed on 12/10/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 02/13/2024, 02/13/2024, 11/24/2025 are being considered by the examiner.
Claim Interpretation
As no specific structural requirement has been identified by the specification to provide for the function of the inhibition of ALDH1A3 the examiner has interpreted the claims to assume that any compounds of the generic formula of claim 67 inhibits ALDH1A3. This then assumes that any compounds of this formula inherently inhibit ALDH1A3. If this is untrue there would be a 112(a) rejection because the applicants have not enabled the selection of which compound would inhibit ALDH1A3.
Specification
The disclosure is objected to because it contains an embedded hyperlink (page 4 (see, e.g., https://portals.broadinstitute.org/ccle; Chefetz, 2019) and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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.
Claim 86 is 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 a cause by an aberrant expression of ALDH1A3, type II diabetes cause by an aberrant expression of ALDH1A3, or a cardiovascular disorder cause by an aberrant expression of ALDH1A3 does not reasonably provide enablement for cancer without aberrant ALDH1A3 or where better survival (rather than worse) is achieved with ALDH1A3 inhibition. As another example, it is unlikely to work for type 1 diabetes (where cells destroyed by autoimmune attack) or for any of the claimed conditions unrelated aberrant ALDH1A3 . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
[In re Sichert, 196 USPQ 209 (CCPA 1977)]
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).[1]
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
1. The nature of the invention, state and predictability of the art, and relative
skill level
The invention relates to a method of treating a proliferative disorder, obesity or complication of obesity, diabetes or a cardiovascular disorder comprising administering to a subject a compound of claim 67. The relative skill of those in the art is high, that of an MD or PHD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, the examiner cites the fact that while Applicant demonstrated the use of compound ALDHI-1001-3014 in ALDH selectivity assay, nowhere in the specification did applicant demonstrate the use of various types of compounds of the claim 67 formula that are structurally divergent. For example, the Formula teaches a compound wherein Ring B1 is a non-aromatic monocyclic heterocyclic ring having 7 ring atoms; and yet nowhere did applicant demonstrate any of those substructures in a ALDH selectivity assay. Given that such compounds would have contrasting chemical and/or physical reactivity and given the nature of the invention, the examiner maintains that applicant has yet to enable the use of various compounds encompassed by the generic formula. Additionally, the examiner contends that the term cancer encompasses various type of cancers and yet applicant failed to provide enablement for various cancers utilizing the various compounds of the generic formula including those not related to ALDH1A3. Further, the predictability of treating cancer is relatively low given that the various types of cancers have different causative agents, involve different cellular mechanisms, and consequently, differ in treatment protocol. It is known (see Jin et al., Nature Reviews Drug Discovery | Volume 22 | March 2023 | 213–234) in the current art that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, to maximize efficacy and minimize toxicity. Thus, given that applicant has failed to demonstrate treatment of various cancers utilizing various compounds encompassed by the formula of claim 67 and in light of the challenge in treating various types of cancers and other disease that have different causes, the examiner maintains that applicant has not enabled the breadth of the claims.
2. The breadth of the claims
The claims are thus very broad insofar as they recite a method of treating a proliferative disorder, obesity or complication of obesity, diabetes or a cardiovascular disorder comprising administering to a subject a compound of claim 67. While such “treatment” might theoretically be possible for treating a proliferative disorder cause by an aberrant expression of ALDH1A3, type II diabetes cause by an aberrant expression of ALDH1A3, or a cardiovascular disorder cause by an aberrant expression of ALDH1A3, as a practical matter it is nearly impossible to achieve a treatment for all possible cancers, obesity or complication of obesity, diabetes and cardiovascular disorders with the same compounds of the generic formula of claim 67 especially given the divergent structures of said compounds.
3. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides no direction or guidance for the use of all compounds of claim 67 generic Formula and all cancers and disease subtypes. No reasonably specific guidance is provided concerning useful therapeutic protocols for all of the disclosed compounds of the formula, other than pages 155-162.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of experimental evidence, no one skilled in the art would accept the assertion that every instantly claimed compound of the generic formula could be predictably used for the treatment of every single cancer and/or treating every disease claimed for killing every single cell as inferred by the claims and contemplated by the specification. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
[1] As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is “undue”, not “experimentation”.
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 86 is 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.
Regarding claim 86, the phrase "including" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 74-75 and 83 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 74-75 are dependent claims citing claim 73. However, "thiazolyl" has three carbon atoms forming the ring. Therefore, claims 74 and 75 have an inappropriate relationship with claim 73, which specifies "ring A is a C5 heteroaryl group." . Claim 83 improperly broadens claim 67 because claim 67 has a proviso removing compound ALDHI-1008 from claim 67, however, claim 83 includes this compound. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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) 83 is/are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by STN (STN, CAS Registry Number: 2249547-39-3 REGISTRY Entered STN: 19 Nov 2018).
The reference STN teaches the following compound, which is the same compound as ALDHI-1008 in claim 83. This anticipates claim 83.
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885
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Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 68-82 and is/are rejected under 35 U.S.C. 103 as being unpatentable over TAKASUGI (TAKASUGI et al., WO02090347A1, 2002-11-14).
The reference TAKASUGI teaches the following lead compound (Preparation 80, page 109-110), wherein Q=OCH2, R1=R3=R4=H, J=
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121
198
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, A= aromatic 6 membered ring, M1=phenyl, RM1c=C1haloalkyl. This is not a 102(a) rejection because there is a proviso against this compound being included in the instant claims( PROV-A-02), however, this is still a 103 because this can still be used as a lead compound in combination with the general formula for the reference to produce similar compounds that are obvious derivatives of this lead compound that have no proviso against them. This helps to teach claim 67, 69, 77.
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The reference TAKASUGI teaches the following general formula(reference claims 1-2, 4 and page 20):
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195
518
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193
739
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29
630
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192
613
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88
543
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164
696
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219
654
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102
675
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171
1454
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This helps to teach claims 68, 73, 74, 75,76, 78, 79, 80, 81, 82.
The TAKASUGI reference also teaches “For therapeutic administration, the object compound (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral or external administration. The pharmaceutical preparation may be compounded in a solid form such as granule, capsule, tablet, dragee, suppository or ointment, or in a liquid form such as solution, suspension or emulsion for injection, intravenous drip, ingestion, eye drop, etc”(page 57). This helps to teach claim 84.
The TAKASUGI reference also teaches “Still further object of this invention is to provide a use of said amide compounds or pharmaceutically acceptable salts thereof as a medicament for prophylactic. and therapeutic treatment of diseases or conditions resulting from elevated circulating levels of Apo B, such as hyperlipemia, hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), obesity, coronary heart diseases, myocardial infarction, stroke, restenosis and Syndrome X”(pages 1-2). This helps to teach claims 85-86.
The reference TAKASUGI does not specifical teach a compound of the instant invention instead it teaches a lead compound that has a proviso against it and a general formula that provides obvious modifications that would give compounds of the instant claims(all claims).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified TAKASUGI to get compounds of the instant invention because the lead compound can be obviously modified based on the general formula to provide all the compounds of the instant claims for instance to get around the proviso all that is needed and provided for by the general formula is to add a methyl which is considered an obvious modification since the structure is so similar one would be have a reasonable expectation that it would also have the function to treat the same diseases and so one would be motivated to do so. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). It is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963). Since it would be obvious to produce a compound of the instant invention and use that compound for treatment of a disease that same compound, since it would be a compound of the instant invention, would inhibit ALDH1A3 even if that property was not known. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess the characteristic relied on” (205 USPQ 594, second column, first full paragraph).
Claim(s) 67-71 and 84-86 is/are rejected under 35 U.S.C. 103 as being unpatentable over TOMINAGA (TOMINAGA et al., JPS5780322 A, 1982-05-19) as evidenced by Scifinder CAS 82699-27-2 (Cardiotonic formulations containing aminoalkoxydihydrocarbostyrils, JP57080322 A, 1982-05-19).
The reference TOMINAGA teaches the following compound (scifinder CAS 82699-27-2 ), wherein Q =CH2CH2, R1= R3=R4=H, J=
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107
207
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, RJ1-RJ5=H, M2=phenyl.
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126
511
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.
The reference TOMINAGA teaches the following general formula(page 1) and “R2 and R3 each represent a hydrogen atom, a lower alkyl group which may have a hydroxyl group as a substituent, a phenyl lower alkyl group”(page 1). This helps to teach claims 67-71.
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The reference TOMINAGA teaches “As a result of further research, the present inventors have found that the carbostyril derivatives of the above general formula (1) have effects that cannot be predicted from their antibacterial, anti-inflammatory, platelet aggregation inhibitory, lipid content reducing, central nervous system depressant and antistaminic effects, namely, the effect of enhancing myocardial contraction (positive inotropic effect) and the effect of increasing coronary blood flow, and therefore are effective as cardiotonic agents for the treatment of heart diseases such as congestive heart failure, amplified valvular disease, atrial fibrillation, flutter and paroxysmal atrial tachycardia. The present invention was completed based on this finding”(page 1) and “The formulation is prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc. Various forms of this pharmaceutical preparation can be selected depending on the purpose of treatment, and representative examples include tablets, split tablets, powders, liquids, suspensions, emulsions, granules, injections, capsules, and injections (liquids, suspensions, etc.)”(page 32). This helps to teach claims 84-86.
The reference TOMINAGA does not specifical teach a compound of the instant invention where RJ3 is not H instead it only teaches a lead compound wherein RJ3=H and a general formula wherein RJ3= alkyl group (all claims).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified TOMINAGA to make a compound of the instant claims by modifying the lead compound by replacing RJ3=H to RJ3=methyl because such a change is suggested by TOMINAGA general formula I (page 1). One would be motivated to do so to make cardiotonic agents for the treatment of heart diseases and one would have reasonable expectation of success because a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). It is generally noted that the substitution of methyl for hydrogen on a known compound is not a patentable modification absent unexpected or unobvious results. In re Druey, 319 F.2d 237, 138 U.S.P.Q. 39 (C.C. P.A. 1963). Since it would be obvious to produce a compound of the instant invention and use that compound for treatment of a disease that same compound, since it would be a compound of the instant invention, would inhibit ALDH1A3 even if that property was not known. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter which there is reason to believe includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess the characteristic relied on” (205 USPQ 594, second column, first full paragraph).
Conclusion
Claims 67-86 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR SALAMATIAN whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Kortney Klinkel can be reached at (571) 270-5239. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/A.A.S./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627