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 the Claims
Claims 1-18 are pending. Claims 1-18 are rejected.
Priority
This application is a 35 U.S.C. 371 National Stage Filing of International Application No. PCT/CN2021/128275, filed 11/02/2021. Acknowledgment is made of applicant's claim for foreign priority based on application CN 202011271276.5, filed 11/13/2020. It is noted, however, that applicant has not filed an English translation of the certified copy of the CN 202011271276.5 application as required by 37 CFR 1.55. Therefore, the effective filing date is 11/02/2021.
Information Disclosure Statement
The information disclosure statement filed 04/19/2023 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. In particular, non-patent literature entries 4 and 5, “Notification to Grant Patent Rights for Invention of China Counterpart Application”, issued on July 1, 2022 and “Patent certificate of China Counterpart Application”, issued on August 2, 2022 have not been considered. It has been placed in the application file, but the information referred to therein has not been considered, except where indicated by the Examiner.
Claim Objections
Claims 1-4, 7-9, and 13-18 are objected to because of the following informalities:
Claim 1 is objected to because the use of “and” in the preamble appears to require not only the compound of general formula (I) but also a pharmaceutically acceptable salt thereof, a solvate thereof, etc. The Examiner recommends amending the phrase “and an isomer thereof” to “or an isomer thereof”.
Similarly to claim 1, claims 2-4, 7-9 and 13-18 are objected to because the use of “and” in the preamble appears to require not only the compound of general formula (I) but also a pharmaceutically acceptable salt thereof, a solvate thereof, etc. The Examiner recommends amending the phrase “and the isomer thereof” to “or the isomer thereof”.
Appropriate correction is required.
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 8-9 and 13-18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the phrase “Use of the compound of general formula (I)” is not viewed as a process, machine, manufacture, or composition of matter and therefore does not qualify as a statutory category. See MPEP 2173.05(q).
Claim Rejections - 35 USC § 112(a)
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 1-18 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 a compound of general formula (I), a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, does not reasonably provide enablement for the full scope of “isomers” of compounds of general formula (I). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is undue. These factors include, but are not limited to: (a) breadth of the claims; (b) nature of the invention; (c) state of the prior art; (d) level of one of ordinary skill in the art; (e) level of predictability in the art; (f) amount of direction provided by the inventor; (g) existence of working examples; and (h) quantity of experimentation needed to make or use the invention based on the content of the disclosure. (See Ex parte Forman 230 USPQ 546 (Bd. Pat. App. & Inter. 1986) and In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988).
The above factors, regarding the present invention, are summarized as follows:
(a) Breadth of the claims - The breadth of the claim includes a compound of general formula (I) as well as all isomers thereof. The common meaning of the general term isomer is (Merriam-Webster):
One of two or more compounds, radicals, or ions that contain the same number of atoms of the same elements but differ in structural arrangement and properties.
Accordingly, the scope of “isomers” as a general term would encompass not only stereoisomers such as diastereomers, enantiomers, geometric isomers, etc., but compounds that have the same molecular formula, i.e. same number of carbon atoms, hydrogen atoms, etc., in any configuration. This would include compounds that bear little structural resemblance to a compound having the explicit definition of general formula (I).
The specification, although discussing types of isomers including stereoisomers and optical isomers on page 4, fails to set forth a clear definition that the term as recited in the instant claims should be limited to the examples of the specification.
(b) Nature of the invention - The nature of the invention is drawn to compounds and their isomers for use in treating a disease caused by abnormal neovascularization or as tubulin aggregation inhibitors.
(c) State of the prior art – It is well established that stereoisomers are reasonably expected to have similar properties to a racemate or other mixture of stereoisomers since these compounds have the same functional groups and atom connectivity while differing only slightly in spatial orientation. Constitution isomers are drawn to compounds that have the same molecular formula but differ in atom connectivity. It is well established that constitutional isomers can have wildly different properties since it is the structure of a compound that controls its properties and not its atom count.
(d) Level of one of ordinary skill in the art - The artisans synthesizing applicant’s compounds and isomers would be a collaborative team of synthetic chemists and/or medicinal chemists, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
(e) Level of predictability in the art - Synthetic organic chemistry is quite unpredictable (In re Marzocchi and Horton 169 USPQ at 367 ¶ 3). The following excerpt is taken from Dörwald (Dörwald, F. Zaragoza. Side Reactions in Organic Synthesis: A Guide to Successful Synthesis Design, Weinheim: WILEY-VCH Verlag GmbH & Co. KGaA, 2005, Preface):
Most non-chemists would probably be horrified if they were to learn how many attempted syntheses fail, and how inefficient research chemists are. The ratio of successful to unsuccessful chemical experiments in a normal research laboratory is far below unity, and synthetic research chemists, in the same way as most scientists, spend most of their time working out what went wrong, and why.
Despite the many pitfalls lurking in organic synthesis, most organic chemistry textbooks and research articles do give the impression that organic reactions just proceed smoothly and that the total synthesis of complex natural products, for instance, is maybe a labor-intensive but otherwise undemanding task. In fact, most syntheses of structurally complex natural products are the result of several years of hard work by a team of chemists, with almost every step requiring careful optimization. The final synthesis usually looks quite different from that originally planned, because of unexpected difficulties encountered in the initially chosen synthetic sequence. Only the seasoned practitioner who has experienced for himself the many failures and frustrations which the development (sometimes even the repetition) of a synthesis usually implies will be able to appraise such work.
Chemists tend not to publish negative results, because these are, as opposed to positive results, never definite (and far too copious).
(f) Amount of direction provided by the inventor and Existence of working examples – The application provides direction for the preparation of compounds of general formula (I) and for stereoisomers; however, the application is negligent with respect to making any of the other possible constitutional isomers of compounds of general formula (I). Applicant has provided sufficient guidance to make and use compounds of general formula (I) and stereoisomers thereof; however, the disclosure is insufficient to allow extrapolation of the limited examples to enable the scope of the tens of thousands of constitutional isomers thereof.
Within the specification, “specific operative embodiments or examples of the invention must be set forth. Examples and description should be of sufficient scope as to justify the scope of the claims. Markush claims must be provided with support in the disclosure for each member of the Markush group. Where the constitution and formula of a chemical compound is stated only as a probability or speculation, the disclosure is not sufficient to support claims identifying the compound by such composition or formula.” See MPEP § 608.01(p).
(h) Quantity of experimentation needed to make or use the invention based on the content of the disclosure – Based on the lack of guidance in the instant specification, a person having ordinary skill in the art would be faced with undue experimentation in making and using the full scope of the instant claims. A person having ordinary skill in the art, in seeking to make constitutional isomers for use in treating a disease caused by abnormal neovascularization or as tubulin aggregation inhibitors would be faced with hundreds of possible constitutional isomers. In order to test the properties of these isomers, a person having ordinary skill in the art would need to develop synthetic approaches to these compounds, which can be quite unpredictable as discussed in section (e). Since Applicant only provides guidance as to the particular structural attributes of the general formula (I) that lead to treating a disease caused by abnormal neovascularization or for tubulin aggregation inhibition, a person having ordinary skill in the art would be faced with undue experimentation in attempting to synthesize the numerous structurally dissimilar constitutional isomers instantly claimed in order to find additional inhibitors.
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)}.
The determination that undue experimentation would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. (In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404). These factual considerations are discussed comprehensively in MPEP § 2164.08 (scope or breadth of the claims), § 2164.05(a) (nature of the invention and state of the prior art), § 2164.05(b) (level of one of ordinary skill), § 2164.03 (level of predictability in the art and amount of direction provided by the inventor), § 2164.02 (the existence of working examples) and § 2164.06 (quantity of experimentation needed to make or use the invention based on the content of the disclosure).
Based on a preponderance of the evidence presented herein, the conclusion that applicant is insufficiently enabled for making and using all isomers of compounds of general formula (I) is clearly justified. It is suggested that Applicant amend instant claim 1 to replace “an isomer thereof” with “a stereoisomer thereof” and instant claims 2-5 and 7-18 to replace “the isomer thereof” with “the stereoisomer thereof”.
Claim Rejections - 35 USC § 112(b)
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.
Claims 2, 8-10 and 13-18 are rejected under 35 U.S.C. 112(b) being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Regarding claim 2, the phrases “more preferably” and "even more preferably" renders the claim indefinite because it is unclear whether the limitations following the phrases are part of the claimed invention. See MPEP § 2173.05(d). Applicant may overcome the rejection by amending the claim to delete the indefinite phrases and the limitations that follow.
Dependent claims 10, 13 and 16 are rejected as indefinite for the same reason since they do not correct the indefiniteness issue of their parent claim.
Regarding claims 8-9 and 13-18, each drawn to “Use of the compound of general formula (I)” are viewed as attempts to claim a process without setting forth any steps involved in the process. As such, a skilled artisan would not be able to determine the metes and bounds of the invention in order to avoid infringement. Additionally, to the extent the claims recite a process of using, it is unclear HOW the process must be carried out because there are no active steps. See MPEP 2173.05(q).
Claim Rejections - 35 USC § 112(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.
Claims 2-3, 10-11, 13-14 and 16-17 are rejected under 35 U.S.C. 112(d) 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.
Regarding claim 2, the limitations wherein R2 and R3 are each propenyl or propynyl are not present in parent claim 1. Claim 1 discloses that R2 and R3 are each independently selected from C1-C6 alkyl, a C1-C6 haloalkyl and a C1-C6 alcohol group. Further, the definition of “alkyl” provided on page 8, para. [0030] of the specification does not embrace propenyl or propynyl as understood by a skilled artisan. Therefore, claim 2 includes subject matter outside the scope of parent claim 1. Applicant may overcome the rejection by, for example, deleting the referenced limitations in claim 2.
Dependent claims 10, 13 and 16 are rejected as indefinite for the same reason since they do not correct the improper dependency issue of their parent claims.
Claim 3, which depends from claim 1, recites the compound “(Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-bis(2-n-propyl)amino)propionamide)-4-trifluoroethoxyphenyl)”. See lines 7-8 on page 5. The compound as stated does not properly depend from claim 1 because it does not include the ethylene bridge between the two aromatic rings. It appears as though the claim was intended to recite the name of Example 7 on page 16 of the specification. Applicant may amend the compound name to state “(Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-bis(2-n-propyl)amino)propionamide)-4-trifluoroethoxyphenyl)ethylene” in order to overcome the rejection.
Additionally, claim 3 recites the compound “(Z)-1-(3,4,5-trimethoxyphenyl)-2-((3-(2,2-dimethoxyethylamino)propionamide)-4-ethoxyphenyl)ethylene” in the last three lines of the claim, which corresponds to the following structure:
PNG
media_image1.png
93
302
media_image1.png
Greyscale
. See Example 14 on page 20 of the specification. The recited compound does not properly depend from claim 1 because it has methoxy groups in the R2 and R3 positions of formula (I) of claim 1. While claim 1 recites that R2 and R3 may be alkyl or alcohol groups, neither of these terms embrace the alkoxy group presented in the dependent claim. Applicant may amend the claim by deleting the compound name.
Dependent claims 11, 14 and 17 are rejected as indefinite for the same reason since they do not correct the improper dependency issue of their parent claims.
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 1-18 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Buerger et al. in WO 2010/010138 A1, as evidenced by CAS Registry Number 16662-47-8.
The prior art teaches gallopamil on page 32, claim 3, which has the following structure:
PNG
media_image2.png
204
384
media_image2.png
Greyscale
. See also CAS Registry 16662-47-8.
The compound above has the molecular formula C28H40N2O5, which is the same molecular formula as Example 1
PNG
media_image3.png
106
323
media_image3.png
Greyscale
of general formula (I) of instant claims 1-3. See also page 9, paragraph [0049] of the specification. As discussed above, the term “isomer” is generic to constitutional isomers, i.e. compounds having the same molecular formula.
Regarding instant claim 4 and its dependent claims 12, 15, and 18, wherein the pharmaceutically acceptable salt of the compound of general formula (I) is formed by a basic salt-forming group and an acid wherein the acid is an organic acid, the prior art on page 29, line 21 teaches the HCl salt of gallopamil.
Regarding instant claims 5, its dependent claims 6 and 7, and claims 10-12 drawn to a medicament or pharmaceutical composition, the prior art teaches a pharmaceutical composition of gallopamil on page 34, claim 10 and claim 12 further comprises a composition with pramipexole. Instant claim 6, which depends from claim 5, is further drawn to topical, enteral, or parenteral administration. The prior art teaches a medication on page 35 wherein the medication of claim 3 is for oral administration, which is a type of enteral administration. Instant claim 7 is further drawn to the medicament formulated in a tablet or capsule. The prior art teaches a formulation of gallopamil-HCl on page 29, line 21 wherein the formulation is a bc.1 tablet.
Regarding instant claims 8-9 and 13-18, the recited uses of the compound of general formula (I) for treating a disease caused by abnormal neovascularization or as a tubulin aggregation inhibitor have been interpreted as intended uses which do not carry patentable weight. Therefore, the claims are encompassed in the prior art reference, even though these specific uses are not cited therein.
Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jalisa H. Ferguson whose telephone number is (703)756-1489. The examiner can normally be reached Monday - Friday 9:00am - 5:00pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joseph McKane can be reached on (571) 272-0699. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.H.F./Examiner, Art Unit 1626
/JOSEPH K MCKANE/Supervisory Patent Examiner, Art Unit 1626