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 .
Status of Claims
Claims 80 and 86-93 are pending.
Priority
Instant application 17/632,214, filed 02/01/2022 claims priority as follows:
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The priority documents US Provisional Applications No. 62/882,329, 62/882,313, and 62/895,461 fail to provide support under 35 U.S.C. 112 for the compounds ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, and ENT-011 recited in instant claims 80 and 86-93. The priority document PCT/US2020/04468 contains support for the limitations of claims 80 and 86-93. Therefore, in view of the foregoing, claims 80 and 86-93 are entitled to an effective filing date of 07/31/2020.
Information Disclosure Statement
All references from IDS(s) received 02/01/2022, 03/18/2022, 06/22/2023, 09/21/2023, and 12/11/2024 have been considered unless marked with a strikethrough.
Response to Amendment
The amendment filed 04/02/2025 has been entered. Claim 80 is amended. Claims 1-79 and 81-85 are cancelled. Claims 86-93 are new.
Election/Restrictions
Applicant’s election without traverse of Group III in the reply filed on 04/02/2025 is acknowledged.
Applicant's election with traverse of the species compound ENT-04 in the reply filed on 04/02/2025 is acknowledged. The traversal is on the ground(s) that “the search and examination burden on the Examiner is not undue”.
Applicant’s arguments have been fully considered but are not persuasive. The instant claims are drawn to aminosterol compounds or salts or derivatives thereof. The specification and claims do not define the term “derivative”. Some of the aminosterol compounds are deuterated, for examples ENT-04 and ENT-07, which are deuterated variants of the known compounds trodusquemine and squalamine comprising deuterium at C25-C27 on the cholestane portions. Other compounds recited by the claims are deuterated elsewhere on the cholestane portion such as on the ring carbons C2 and C4 in ENT-09. Finally, the claims recite compounds (ENT-10 and ENT-11) which appear to be oxidized variants of ENT-08 and ENT-09 having no deuterium.
Searching the different species would require different fields of search since multiple different search queries and strategies would be required. Search of compositions comprising the deuterated variants of a compound (or any derivative thereof) requires a different search technique and queries than searching compositions comprising an oxidized form of a compound (or any derivative thereof). In particular, search of a deuterated compound requires examination of unique subclasses, for example C07B2200/05 and C07B 59/00. Additionally, the Examiner needs to search for and consider obviousness art for an invention related to 35 U.S.C. 103, this requires broader and more extensive search queries than those searches for anticipatory art. The motivation for deuterating a molecule may not necessarily be the same as the motivation for oxidizing a particular portion of a molecule. Further, the motivation for deuterating one part of a molecule may not necessarily be the same motivation for deuterating a different portion of the same molecule. Examination of the different species compounds would incur a search and examination burden.
The requirement is still deemed proper and is therefore made FINAL. In the interest of compact prosecution, the species election has been expanded to both the compounds ENT-04 and ENT-07, which are sufficiently close in structure to examine simultaneously.
Therefore, claims 88-91 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. Applicant timely traversed the restriction (election) requirement in the reply filed on 04/02/2025.
Examination will begin with the elected species. In accordance with MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
The elected species were searched and applicable art was identified. Therefore, the entire scope of claims 80, 86-87, and 92-93 has not yet been examined in accordance with Markush search practice. See MPEP 803.02.
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 80, 86-87, and 92-93 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “derivative” in claims 80, 86, and 92-93 is an ambiguous term which renders the claim indefinite. The term “derivative” is not defined by the claim, the specification does not provide a standard for ascertaining the meaning, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The only direction for what the term “derivative” encompasses is provided in the specification at [0074], which states:
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Please note that [0074] generally provides guidance about what an aminosterol derivative can be, but does not provide sufficient guidance to specifically define what a “derivative” of ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, or ENT-011 definitively encompasses. Moreover, the specification fails to provide any examples of a “derivative” of ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, or ENT-011 as claimed.
The scope of claims 80, 86, and 92-93 is therefore unclear because the specification does not sufficiently define a “derivative” of ENT-04, ENT-07, ENT-08, ENT-09, ENT-10, or ENT-011 such that a person having ordinary skill in the could identify if a compound reads on the claims.
For the purposes of prior art, the “derivative” of ENT-04 and ENT-07 is being interpreted as a compound where any atom or group of atoms in ENT-04 and ENT-07 is replaced by a different atom. In particular, the “derivative” of ENT-04 and ENT-07 is being interpreted as encompassing squalamine and trodusquemine, which are derivatives of ENT-04 and ENT-07 where the deuterium atoms are replaced by hydrogen atoms.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 80, 86-87, and 92-93 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more. Claim 80, 86-87, and 92-93 (and claims dependent thereon) are directed to compounds which occur naturally in the dogfish shark Squalus acanthias. The Examiner has followed the guidance set forth in MPEP 2106 and has concluded that the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception.
The instant claims are directed, in part, to “derivatives” of the compounds ENT-04 and ENT-07. In view of the Examiner’s interpretation of the term “derivative”, the compounds squalamine and trodusquemine read on the instant claims. Squalamine and trodusquemine are naturally-occurring in the dogfish shark Squalus acanthias and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. The rationale for this determination is explained below:
Eligibility Step 1: Determine if the claims are directed to one of the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: a process, machine, manufacture or composition of matter. YES, the claims are directed to a composition of matter, which is a statutory category within at least one of the four categories of patent eligible subject matter.
Eligibility Step 2A: PRONG ONE: Evaluate whether the claim recites a Judicial Exception (e.g., law of nature, natural phenomenon, or an abstract idea). YES, the claims are product claims reciting compounds which are nature-based products (i.e., compositions comprising the natural products squalamine or trodusquemine). See, for example, Rao (Journal of Natural Products, vol. 63, no. 5, May 2000, pp. 631–35) which discloses squalamine and trodusquemine (MSI-1436) as natural products isolated from the liver of the dogfish shark.
Eligibility Step 2A: PRONG TWO: Evaluate whether the judicial exception is integrated into a practical application. The claims are directed to a compound or a composition, not its practical use such as a particular treatment or prophylaxis for a disease or medical condition.
Thus, the cited claims are directed to a judicial exception to patentable subject matter.
Eligibility Step 2b: Determine whether the claim directed to a judicial exception provides an inventive concept. For example, the claims may recite additional elements that amount to significantly more than the judicial exception. In the instant case, NO, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception, because there are no “additional elements” required by the present claims since they are directed only to compositions comprising the naturally occurring substances. No other specific limitations other than what is well-understood, routine and conventional in the field at a high level of generality have been added to the claimed nature-based product.
Thus, the claimed product is not eligible subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 80, 86-87, and 92-93 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rao (Journal of Natural Products, vol. 63, no. 5, May 2000, pp. 631–35).
The instant claims are directed, in part, to “derivatives” of the compounds ENT-04 and ENT-07. In view of the Examiner’s interpretation of the term “derivative”, the compounds squalamine and trodusquemine read on the instant claims.
Rao discloses squalamine and trodusquemine (MSI-1436) and compositions comprising squalamine and trodusquemine in deuterated methanol (Table 3, compounds 7 and 8).
Accordingly, claims 80, 86-87, and 92-93 are anticipated by Rao.
Claims 80, 86-87, and 92-93 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Barbut et al. (WO 2020172289 A1; effectively filed 20 February 2019 based on priority claim to US Provisional No. 62/808,067).
The applied reference has common joint inventors with the instant application (Barbut, Zasloff, Kinney), but also names other inventors (Jones, Ashford, Bieliauskas, Hessler, Fevig, and Karnes). Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Barbut is drawn to deuterated forms of aminosterols and methods of using the same, wherein one or more hydrogen atoms at one or more positions selected from Cl, C2, C3, C4, C5, C6, C7, C8, C9, C11, C12, C14, C15, C16, C17, C18, C19, C20, C21, C22, C23, C24, C25, C26, and C27, are replaced with deuterium (title, abstract).
In particular, with respect to Applicant’s elected species, Barbut discloses the compounds (pages 11 and 12, [0021]):
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With respect to claims 92-93, The deuterated compounds disclosed by Barbut above are portrayed with ambiguous stereochemistry for the sulfo group (represented by the wavy bond). The structures appear to represent epimers, i.e. the drawn structures represent a mixture comprising a pair of diastereomers which merely differ by a single stereogenic center. A person having ordinary skill would have recognized that one of the epimers of D7-1436 disclosed by Barbut is ENT-04; and that one of the epimers of D7-squalamine disclosed by Barbut is ENT-07.
Therefore, Applicant’s elected species ENT-04 and ENT-07 are anticipated by Barbut; and Barbut anticipates claims 92-93.
With respect to claims 80 and 86-87, Barbut discloses a pharmaceutical composition comprising a compound according to any one of claim 1-5 (page 184, claim 6). Claim 5 of Barbut recites D7-1436 and D7-squalamine.
Therefore, Barbut anticipates claims 80 and 86.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 80, 87, and 92 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Journal of Pharmaceutical and Biomedical Analysis, vol. 34, no. 3, Feb. 2004, pp. 631–41) in view of Arrivault et al. (Analytical Chemistry, vol. 87, no. 13, July 2015, pp. 6896–904).
Li is drawn to the quantitative analysis of squalamine, a self-ionization-suppressing aminosterol sulfate, in human plasma by LC-MS/MS (page 1, abstract). Li discloses developing a sensitive, accurate, precise, and specific method for the quantitative determination of squalamine in human plasma, wherein deuterated squalamine was used as an internal standard (page 1, abstract).
In particular, Li discloses squalamine and deuterated squalamine, wherein the deuterated squalamine has the structure (Fig. 1):
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The D6-squalamine disclosed by Li differs from ENT-07 of the instant claims by the specific location of deuterium incorporation in the molecule.
However, as taught by Arrivault, the use of stable-isotope-labeled internal standards (SIL-IS), particularly deuterium labeled internal standards for quantification by LC-MS/MS is a routine practice. In particular, Arrivault teaches that SIL-IS can be used to correct for matrix effects in analytical methods (page 6897, left side, 3rd para.):
A SIL-IS is an isotopically labeled form of the metabolite of interest, in which two or more atoms have been substituted by nonradioactive isotopes. The most commonly used isotopes are 2H, 13C, and, to a lesser extent, 15N and 17O. The inclusion of stable isotopes has no significant effect on most of the physicochemical properties of the molecule, so both the labeled and unlabeled forms behave in the same way during sample extraction and chemical derivatization…The unlabeled and labeled isotopomers have essentially identical ionization characteristics. However, following ionization, the resulting ions have different m/z values and so can be readily distinguished by MS. To correct for matrix effects, standard mixes and samples are spiked with a known amount of the SIL-IS before analysis. The labeled and unlabeled forms of the metabolite of interest coelute from the LC and are exposed to identical ionization conditions, including any interference by other molecules, before entering the MS.
Both Li and Arrivault therefore provide a motivation for preparing deuterium labeled internal standards, particularly deuterium-labeled squalamine internal standards.
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (G), it would have been prima facie obvious to prepare a deuterated squalamine compound, such as compound ENT-07 of the instant claims. Li teaches that deuterated squalamine can be used in a method for quantitative analysis of squalamine in human plasma. Further, in view of the teachings of Arrivault that the inclusion of stable isotopes has no significant effect on most of the physicochemical properties of the molecule, so both the labeled and unlabeled forms behave in the same way during sample extraction and chemical derivatization, a skilled artisan would have enjoyed a reasonable expectation of success when applying a different deuterated squalamine compound as the internal standard in Li’s method.
The deuterated squalamine ENT-07 claimed by Applicant has not been shown to possess any unexpected or unpredictable properties, particularly properties which can be attributed to the position of deuterium incorporation in the molecule.
Therefore, absent evidence to the contrary, claims 80, 87, and 92 are prima facie obvious over Li in view of Arrivault.
Claims 86 and 93 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Journal of Pharmaceutical and Biomedical Analysis, vol. 34, no. 3, Feb. 2004, pp. 631–41) in view of Arrivault et al. (Analytical Chemistry, vol. 87, no. 13, July 2015, pp. 6896–904) applied to claims 80, 87, and 92 above, further in view of Rao et al. (Journal of Natural Products, vol. 63, no. 5, May 2000, pp. 631–35).
The teachings of Li in view of Arrivault are disclosed above and at least those teachings are incorporated herein by reference. Li in view of Arrivault teach deuterium-labeled squalamine as internal standards for quantifying squalamine in human plasma.
Rao is drawn to aminosterols from the Dogfish Shark Squalus acanthias and discloses squalamine (abstract and Fig. 1, compound 8) and MSI-1436, also known as trodusquemine (abstract, compound 7). Rao discloses that both squalamine and trodusquemine possess comparable antimicrobial activity (abstract).
Applying KSR example rationale (G), it would have been prima facie obvious to modify the method for analyzing squalamine in human plasma to instead analyze trodusquemine in human plasma. A skilled artisan would have been motivated to analyze trodusquemine in human plasma to acquire toxicology and pharmacokinetic parameters as taught by Li. Further, in view of the teachings of Li and Arrivault, a skilled artisan would have enjoyed a reasonable expectation of success when applying a deuterated trodusquemine compound as the internal standard in the modified method taught by Li.
The deuterated trodusquemine ENT-04 claimed by Applicant has not been shown to possess any unexpected or unpredictable properties, particularly properties which can be attributed to the position of deuterium incorporation in the molecule.
Therefore, absent evidence to the contrary, claims 86 and 93 are prima facie obvious over Li in view of Arrivault, further in view of Rao.
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 80, 86-87, and 92-93 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-15, 17-18, 20, and 24-25 of copending Application No. 18/877,724 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application recites a composition comprising ENT-04 or ENT-07 in claim 24 on page 27. Therefore, the instant claims are anticipated by claims of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Claims 80, 86-87, and 92-93 are rejected. Claims 88-91 are withdrawn. No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 8:30 am - 5:30 pm.
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/K.N./Examiner, Art Unit 1621
/BRANDON J FETTEROLF/Supervisory Patent Examiner, Art Unit 1600