DETAILED ACTION
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.
Status of Priority
This application is continuation application of U.S. Application No. 17/975,214 filed October 27, 2022 (and issued as U.S. Pat. No. 12,065,435 on August 20, 2024), which is a continuation application of U.S. Application No. 17/334,905 filed May 31, 2021 (and issued as U.S. Pat. No. 11,891,381 on February 6, 2024), which is a divisional application of U.S. Application No. 16/485,577 filed August 13, 2019 (and issued as U.S. Pat. No. 11,053,231 on July 6, 2021), which is a National Phase of PCT Patent Application No. PCT/IL2018/050207 having International filing date of February 22, 2018, which claims the benefit of priority of U.S. Provisional Application No. 62/461,884 filed on February 22, 2017.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Scope of Enablement
Claims 1-5 and 7-18 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 pharmaceutical composition comprising a compound selected from:
PNG
media_image1.png
461
753
media_image1.png
Greyscale
Compound 19, and
a compound represented by Formula II:
PNG
media_image2.png
626
1498
media_image2.png
Greyscale
,a tautomer or a pharmaceutically acceptable salt thereof, wherein
R6a to R6c, R7, R8a to R8c, independently and in each occurrence represent at least one substituent comprising or being selected from the group consisting of hydrogen and non-substituted C1-6 alkyl and
R9a to R9h independently and in each occurrence represent one or more substituents comprising or being selected from the group consisting of hydrogen or C1-6- alkyl
and a pharmaceutically acceptable carrier;
The pharmaceutical compositions as recited in instant claims 2-5, however, instead of being dependent on instant claim 1, the specification is only enabling for instant claims 2-5 wherein the claims are dependent on point (1) (from above) instead, in addition to the limitations recited in instant claims 2-5;
A method of treating a glycogen storage disease in a subject in need thereof, the method comprising administering to said subject, a pharmaceutical composition as recited in point (1) above;
The method as recited in instant claims 8-12 and 16-18, however, instead of being dependent on instant claim 7, the specification is only enabling for instant claims 8-12 and 16-18 wherein the claims are dependent on point (3) (from above) instead, in addition to the limitations recited in instant claims 8-12 and 16-18;
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. 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 the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “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.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed to make and use the invention based on the content of the disclosure, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims pharmaceutical compositions utilizing compound 19 or the compounds represented by general Formula II, as described in the instant specification, and using these compositions for the treatment of glycogen storage disorders.
State of the prior art and the predictability or lack thereof in the art
According to STN, the earliest reference that discusses instant compound 19 (see instant claim 1 for structure) and the compound of instant Formula IIa (see instant claim 6 for structure) is the instant application:
PNG
media_image3.png
366
658
media_image3.png
Greyscale
PNG
media_image4.png
59
471
media_image4.png
Greyscale
Of these 2 references, the earliest reference is the instant application
PNG
media_image5.png
198
658
media_image5.png
Greyscale
PNG
media_image6.png
113
224
media_image6.png
Greyscale
PNG
media_image7.png
59
469
media_image7.png
Greyscale
This 1 reference that discusses the compound with CAS RN 1269216-79-6 (i.e., instant compound 19) is the instant application
According to STN, there is no prior art that explicitly discloses, before the effective filing date of the claimed invention:
a pharmaceutical composition comprising instant compound 19 or the compound of instant Formula IIa (or any compound encompassed by instant Formula II) with a pharmaceutically acceptable carrier and
a method of treating a medical condition selected from the group consisting of a neurodegenerative disease, an inflammatory disease, a glycogen associated cancer, and a glycogen storage disease in a subject in need thereof, the method comprising administering to said subject, a pharmaceutical composition comprising instant compound 19 or a compound of instant Formula II and a pharmaceutically acceptable carrier.
Further, the state of the art demonstrates that the biological activity of the claimed compositions was highly unpredictable. The instant specification describes a high-throughput screening for compounds able to reduce polyglucosan body (PB) within the skin fibroblasts from an Adult Polyglucosan Body Disease (APBD) patient using 10,084 commercially available compounds obtained from the ChemBridge DiverSet CL library (para. 037). Only 85 compounds were selected as hits (para. 037) which were then subjected to further screening to identify 11 compounds that can reduce cell associated PB mean intensity via a biphasic dose dependent manner (para. 0227) and 8 compounds that can lower PB levels through a monophasic (i.e., a non-dose-responsive) manner (para. 0228).
Thus, the instant specification itself did not identify the compounds of the claimed compositions based upon any known structure-activity relationship. Rather, the compounds were identified empirically from among more than ten thousand chemically diverse molecules through phenotypic screening.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating therapeutic efficacy of compounds.
The breadth of the claims
The claims are broad insofar as the instant claims recite a pharmaceutical composition comprising a compound of instant Formula II wherein the compound can possess a structurally diverse range of chemical groups wherein the chemical groups themselves can also be substituted with any substituent.
The claims are further broad insofar as the instant claims also recite a method of treating a medical condition selected from a wide and diverse set of disease categories including a neurodegenerative disease, an inflammatory disease, a glycogen associated cancer, and a glycogen storage disease, wherein each disease category further encompasses numerous distinct diseases.
The presence or absence of working examples
The instant specification only provides 3 specific examples of compounds encompassed by instant claim 1 which include:
Compound 19:
PNG
media_image1.png
461
753
media_image1.png
Greyscale
Compound 27:
PNG
media_image8.png
168
536
media_image8.png
Greyscale
and
Compound 28:
PNG
media_image9.png
152
497
media_image9.png
Greyscale
.
The working examples do not adequately represent the full breadth of the claimed genus which was established to be broad (see “4. The breadth of the claims” subsection above). For example, according to instant claim 1, R6a to R6c, R7, and R8a to R8c can be any of the substituents listed in instant claim 1, wherein each substituent can also be further substituted with any substituent. However, in the instant case, there is only one working example of a compound encompassed by instant Formula II. Accordingly, significant portions of the claimed structural space remain unexplored by the working examples. The examples, therefore, do not provide any information on how variations in the substituents of a compound represented by instant Formula II can affect the PB-reducing property of the resulting compound across the full scope of the claimed genus. Instead, the instant specification only provides three specific data points for the three specific compounds (i.e., instant compounds 19, 27, and 28 as listed in instant Fig. 2C).
Additionally, the working examples do not adequately represent the full breadth of the claimed methods of treatment. The instant specification demonstrates that selected compounds can reduce PB levels in fibroblasts derived from an APBD patient’s skin and disclose how those specific compounds affect GS activity (instant example 1). The instant specification also performed an ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis on the selected compounds (instant example 2). The instant specification, however, does not provide working examples demonstrating therapeutic activity of the compounds of instant claim 1 in glycogen associated cancers, different neurodegenerative disease models, and inflammatory diseases as encompassed by the claims.
The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure
The amount of direction and guidance provided in the instant specification is insufficient to enable a POSITA to make and use the full scope of the claimed invention without undue experimentation. While the specification describes a high-throughput screening assay used to identify compounds capable of reducing polyglucosan body (PB) levels in fibroblasts derived from an adult polyglucosan body disease (APBD) patient, the specification does not disclose any general scientific principle, structure-activity relationship, or common structural feature that would permit a person of ordinary skill in the art to reasonably predict which additional compounds encompassed by instant Formula II would possess the claimed therapeutic activity.
Instead, the instant specification demonstrates that the claimed compounds were identified by empirically screening 10,084 chemically diverse compounds obtained from the ChemBridge DiverSet CL library. Only 85 compounds were selected as hits (para. 037) which were then subjected to further screening to identify 11 compounds that can reduce cell associated PB mean intensity via a biphasic dose dependent manner (para. 0227) and 8 compounds that can lower PB levels through a monophasic (i.e., a non-dose-responsive) manner (para. 0228).
The instant specification itself acknowledges uncertainty regarding the mechanism of action. Specifically, the instant specification states that 13 of the 19 compounds that can reduce PB levels (i.e., the 11 biphasic hits and the 8 monophasic hits combined are the 19 compounds) can “significantly reduce GS activity by over 30%. This may suggest that the inhibitory effect observed in PB reduction for most hits in cells is due to direct inhibition of the GS enzyme alone, or in combination with other modes of action, such as PP1 inhibition” (para. 0232). Thus, the specification merely proposes possible mechanisms of action rather than establishing a common mechanism by which the hit compounds reduce PB levels (note: Figure 4A shows that the remaining 6 hit compounds either did not reduce or even increased GS activity which shows that reducing GS activity is not the only mechanism that leads to reduced levels of PB; however, the instant specification does not perform any other experiments revealing other mechanisms that the hit compounds are involved in that contributes to the reduction of PB levels).
Accordingly, because the instant specification does not identify the mechanism responsible for the observed PB reduction, nor identify a common structural or functional feature amongst compounds associated with such activity, a POSITA is left without a predictive framework for determining which compounds encompassed by the broad scope of Formula II would possess the claimed therapeutic activity. As a result, a POSITA would require undue experimentation to identify operative compounds and to determine whether such compounds are effective for treating the broad range of diseases encompassed by the claims.
Furthermore:
No prior art published before the effective filing date of the instant invention was found describing a relationship between polyglucosan bodies (PB) and prion disease (a type of neurodegenerative disease). Accordingly, the instant specification’s demonstration that compositions encompassed by instant claim 1 reducing PB levels in Adult Polyglucosan Body Disease (APBD)-derived assays does not reasonably establish that such compositions would be effective for treating neurodegenerative diseases generally.
No prior art published before the effective filing date of the instant invention was found describing a relationship between polyglucosan bodies (PB) and asthma (a type of inflammatory disease). Accordingly, the instant specification’s demonstration that compositions encompassed by instant claim 1 reducing PB levels in APBD-derived assays does not reasonably establish that such compositions would be effective for treating inflammatory diseases generally.
The prior art has established that glycogen metabolism has a key role in the cancer microenvironment (see title and abstract of Zois, C. E. et al. Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy. Journal Mol Med 2016, 94, 137-154.). However, the prior art does not establish a correlation between reducing PB levels in APBD-derived assays with treating any glycogen-associated cancer. Accordingly, the instant specification’s demonstration that compositions encompassed by instant claim 1 reducing PB levels in APBD-derived assays does not reasonably establish that such compositions would be effective for treating any glycogen-associated cancer generally.
Therefore, practicing the full scope of the instant compositions and method claims extends beyond routine optimization and would require a substantial medicinal chemistry research program to identify operative species within the claimed genus, thereby amounting to undue experimentation.
Written Description
Claims 1-5 and 7-18 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.
The breadth of the claims
See “4. The breadth of the claims” subsection of the “Scope of Enablement” section above.
The presence or absence of working examples
See “5. The presence or absence of working examples” subsection of the “Scope of Enablement” section above.
State of the prior art and the predictability or lack thereof in the art
See:
“2. State of the prior art and the predictability or lack thereof in the art” subsection and
the three bullet points from the “6. The amount of direction or guidance present and the quantity of experimentation needed to make and use the invention based on the content of the disclosure” subsection
within the “Scope of Enablement” section above.
The instant specification does not demonstrate that the inventor(s), at the time the application was filed, had possession of the claimed invention
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the instant case, the specification only provides 3 specific examples of compounds (instant compound 19, as recited in instant claim 1, and compounds of instant claim 6), all of which are confined to a very narrow subgenus. According to the MPEP, a very narrow subgenus of compounds does not adequately reflect a claimed genus that is structurally diverse (i.e., broad) and from an invention in an unpredictable art. In the instant case, the instant claims are broad as explained in “4. The breadth of the claims” subsection of the “Scope of Enablement” section above.
Accordingly, the disclosed species do not adequately reflect the structural diversity of the claimed genus and do not demonstrate possession of the full scope of the pharmaceutical composition as recited in instant claims 1-5 and 7-18.
The instant specification also fails to demonstrate possession of the full scope of the claimed therapeutic methods.
The claimed methods encompass treatment of broad disease classes, including any glycogen-associated cancers, any neurodegenerative diseases, and any inflammatory diseases. These disease classes encompass diseases having diverse pathological mechanisms. Furthermore, the instant specification does not provide representative examples demonstrating treatment of different cancer types, neurodegenerative or inflammatory disease models using pharmaceutical compositions disclosed in instant claim 1.
As discussed above, neither the instant specification nor the state of the prior art establishes that reduction of PB levels in APBD-derived assays is predictive of therapeutic efficacy in diseases encompassed by the broad disease categories recited in the instant claims including prion disease, asthma, or glycogen-associated cancers. In the absence of such a recognized relationship, the instant specification’s disclosure that selected compounds reduce PB levels in APBD-derived assays would not reasonably convey to a POSITA that the instant specification was in possession of methods of treating any neurodegenerative disease, any inflammatory disease, and any glycogen-associated cancers by administering the instantly claimed pharmaceutical compositions.
Note on 35 USC § 102 and § 103 Rejections
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.
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.
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.
Claims 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over:
STN registry entry, RN 1332162-29-4 entered into the database on September 14, 2011.
Instant formula IIa (as recited in instant claim 6 and also encompassed by instant Formula II as recited in instant claims 1-5), was publicly available prior to the effective filing date of the instant application:
PNG
media_image10.png
366
655
media_image10.png
Greyscale
. Specifically, the compound was entered into the STN database and was commercially available from ChemBridge Corporation before February 22, 2017. Although the prior art does not expressly disclose a pharmaceutical composition comprising Formula IIa and a pharmaceutically acceptable carrier, it would have been obvious to a POSITA before the effective filing date of the claimed invention to prepare such a composition. Commercially available small molecules are routinely dissolved in suitable solvents during ordinary handling including, for example, synthesis, purification, characterization, storage, and distribution. DMSO was well known in the art as a solvent for small organic molecules and was also recognized as a pharmaceutically acceptable carrier/excipient (See 1st sentence of the following article: McKim et al. Dimethyl Sulfoxide USP, PhEur in Approved Pharmaceutical Products and Medical Devices. Pharmaceutical Technology. 2008, 32.). Accordingly, it would have been obvious to one of ordinary skill in the art to prepare a composition comprising Formula IIa and DMSO, thereby arriving at a pharmaceutical composition comprising a compound of instant claim 1-6 and a pharmaceutically acceptable carrier.
The motivation to prepare such a composition would not have required knowledge that instant Formula IIa possessed therapeutic activity. Rather, the motivation to prepare such a composition would have arisen from the routine handling, preparation, characterization, or storage of commercially available small molecules using conventional solvents well known in the art. Employing DMSO as the carrier merely represents the use of a known carrier to solubilize instant Formula IIa to produce a predictable result of a composition that would be, for example, prepared for 1H NMR characterization.
Conclusion
No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTEN ROMERO whose telephone number is (571)272-6478. The examiner can normally be reached M-F 9:30 AM - 6:00 PM ET.
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, JEFFREY H. MURRAY can be reached at (571) 272-9023. 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.
/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
Prosecution Insights