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 .
DETAILED ACTION
Claims 1, 3, 4, 6, 11, 13, 18, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, 94. 96 and 100 are pending
Claims 96 and 100 are withdrawn from examination as being drawn to a nonelected specie.
Claims 1, 3, 4, 6, 11, 13, 18, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, and 94 are under consideration in the instant office action.
Election/Restrictions
Applicant’s election of Group I (claims 1, 3, 4, 6, 11, 13, 18, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, and 94) and the following species in their response dated 08/21/2026 is acknowledged.
PNG
media_image1.png
287
481
media_image1.png
Greyscale
Upon further consideration, the election of specie requirement is withdrawn. . Claims 96 and 100 are withdrawn from examination as being drawn to a nonelected species.
Claims 1, 3, 4, 6, 11, 13, 18, 25, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, and 94 are under examination and the requirement for restriction is made final.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/10/2024 and 08/21/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application is a U.S. National phase application under 35 U.S.C 371 of PCT application PCT/US2022/046386, filed 10/12/2022, which claims priority under 35 U.S.C 119 (e) from provisional application serial No. 63/255272, filed 10/13/2022.
Claim Objections
Claim 93 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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, 3, 4, 6, 11, 13, 18, 25, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, and 94 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the elected certain species such as those listed in instant claim 93 and the following species, E6 in the table below as taught by Pitterna et al. (US 8110684) referenced in the instant IDS
PNG
media_image2.png
385
542
media_image2.png
Greyscale
And the following compouind from Harris et al. (WO2008/033460, cited in instant IDS)
PNG
media_image3.png
218
293
media_image3.png
Greyscale
is not considered enabled for the other compound species encompassed by 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 use the invention commensurate in scope with these claims.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention and Breadh of the claims: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claims are drawn to compounds of formula (I) shown below, all of which are claimed to be useful in the method of activating glucocerebrosidase.
PNG
media_image4.png
219
276
media_image4.png
Greyscale
PNG
media_image5.png
482
663
media_image5.png
Greyscale
PNG
media_image6.png
481
663
media_image6.png
Greyscale
The formula contains R groups which include heteroaryl, heterocyclyl, alkyl, aryl or carbocycle or nitrogen protecting groups.. In addition, these variables include substituted and unsubstituted functional groups where in the claims does not define what and where the substitutions are in the groups as recited below:
As such the compounds of the claim encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the millions given the number of possible rings, ring systems and substitutions covered by the claims' scope along with varying choices for remaining variables.
As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation”. Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry our the invention commensurate with the scope of his claims". Amgen, In.c, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to act as agents which activate glucocerebrosidase. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response.
Just taking into example the heterocyclic substitutions of the variables in the compounds, although the field of synthetic heterocyclic chemistry has several named reactions applicable to C, H, O, N, X, and S functional groups. Further, the term heterocyclyl in the instant application can encompass mono or fused systems with 3-14 ring members and one or more N, O, or S heteroatoms which may be substitutes. Lack of definition of the substituents in the claim indicates that this substituent can be any group of any size. This definition as such includes a wide range of complex heterocycles which are difficult to synthesize.
However the state of the art of formula (I) as instantly claimed with several substituted or unsubstituted moieties is very poor.
Accordingly, at the time the invention was made, the relative skill of those in the art tasked with identifying compounds exerting an activity of interest would have been high, as the ordinarily skilled artisan would have had, at minimum, a Ph.D. and experience with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods. Deciding which technique to use would have been determined by the skilled artisan’s knowledge regarding the compound and target of interest. Ligand based drug design relies on knowledge of a compound or compounds of interest (i.e., ligands) to derive new compounds that will, in theory, similarly interact with the target of interest to elicit the activity of interest. Conversely, structure based drug design relies on knowledge of the three dimensional structure of the target of interest (i.e., receptor, ion channel, or enzyme) to derive new compounds that will, in theory, interact with the target of interest to elicit the activity of interest. In either case, the compounds derived from these techniques (applied alone or in combination) are then subjected to in vitro testing for validation.
The Level of Predictability in the Art: Once a compound has been identified by ligand based and/or structure-based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target: ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The invention is pharmaceutical in nature as it involves activation of the glucocerebrosides. The skilled artisan would view that the synthesis of all possible variations of the compounds of formula (I) would require much experimentation. The level of predictability in the synthetic chemistry art is low given that a change of substituent, reagent, catalyst in a reaction can lead to very different reaction products and/or different regioselectivity of the reaction. This being the case, one of ordinary skill in the art would not have reasonable assurance that each possible compound claimed in the instant application would be feasible to make and use. It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved" and physiological activity is generally considered to be unpredictable. Pharmaceutical art is unpredictable and target compounds need to be individually assessed for viability.
The Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification in discloses 1147 structurally related compound species encompassed by Formula (I) all of which have the following substituents in common.
R1 = pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl
and R1 and/or A is always substituted by -CF3 or similar In substituent A the R2 and R3 form a specific ring, furthermore, it is substituted by specific substituents, i.a. -CH2-CHF2
R1 and RA do not comprise a "nitrogen protecting group" or consist of a mere alkyl group. The application however support to only a limited numbers of such compounds.
Also the bicyclic spiro core structure is too broadly defined, the examples show some variation, however, many more options are encompassed (e.g. X and Y can be next to each other), also the position of the two main substituents is not defined.
Although there is a high number of examples most of them show little variation and at present in particular R1 and A are too broadly defined. The minimum requirement of the molecules is such that in many cases it cannot even be distinguished which part is -G-R1 and which is -L-A
Applicants further provide synthetic procedures for the 91 compounds (pages 43-49 of the instant disclosure). It is also noted that the nitrogen protecting groups as claimed are not clear and defined in the compounds.
As such it is noted that there is no enablement in the specification wherein the groups for R1 and A of formula (I) comprises heteroaryl groups other than Pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl or any other heteroaryl or heterocyclic groups. Further the substitutions as claimed can be highly varied and different and the specification does not provide any enablement for that.
Amount of Experimentation Necessary and conclusion: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to act in the method of activating glucocerebrosidase. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formula (I) with respect to the disclosure since Formula (I) encompasses thousands or millions of compound species, whereas the instant Specification discloses only 91 such compound species all of which have a similar core. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the hundreds of millions of compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure of 91 compounds. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Thus, in order to identify usable compounds of Formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 91 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (I) for in vitro testing. At this point, however, even "the top scoring molecule could fail in vitro assays and “hit rates are on the order of one in ten”, It is highly unpredictable whether any compound within the subgenus of compounds of Formula (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of claimed compounds encompassed by Formula (I) are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
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, 3, 11, 13 and 94 are rejected under 35 U.S.C. 102 (a) (1) and under 35 U.S.C 102(a)(2) as being anticipated by Pitterna et al. (al. (US 8110684 )
Instant claims are drawn to compounds
PNG
media_image4.png
219
276
media_image4.png
Greyscale
PNG
media_image5.png
482
663
media_image5.png
Greyscale
PNG
media_image6.png
481
663
media_image6.png
Greyscale
Pitterna et al. discloses the following compound E6 which is anticipated by the compound of formula (I) instantly claimed and as such anticipates the instant claim.
PNG
media_image2.png
385
542
media_image2.png
Greyscale
Therefore the compound disclosed by Pitterna et al. fully anticipates instant claims 1, 3, 11, 13 and 94
Claim 1 and 94 are rejected under 35 U.S.C. 102 (a) (1) and under 35 U.S.C 102(a)(2) as being anticipated by Harris et al. (WO 2008/033460)
Instant claim is as stated above
Harris et al. disclose compound 94 which is a specie which falls within the genus of compound of formula (I) instantly claimed and as such anticipates the claim.
PNG
media_image3.png
218
293
media_image3.png
Greyscale
Therefore the compound disclosed by Harris et al. fully anticipates instant claims 1 and 94.
Conclusion
Claims 1, 3, 4, 6, 11, 13, 18, 33, 35, 38, 40, 48, 49, 58, 62, 76, 93, 94 are rejected. Claim 93 is objected to and no claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAVITHA M RAO/Primary Examiner, Art Unit 1691
Prosecution Insights