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 1-15 are pending.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/EP2023/050883, filed on January 16, 2023. This application also claims the benefits of foreign priority to EP22151820.2, filed on January 17, 2022 and EP22170332.5, filed on April 27, 2022.
Specification - Abstract
The abstract of the disclosure is objected to because it is not in compliance with 37 C.F.R. 1.72 (b). Specifically, the sheet presenting the abstract includes other parts of the application or other material. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Applicant is reminded of the proper content of an abstract of the disclosure.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
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 Objections
Claims 3, 5, 7, and 15 is objected to because of the following informalities:
To maintain proper grammar, claim 3 should read:
“…wherein the crystalline form of compound IM-315 is characterized by…”
The instant claims should be written in singular form. Therefore, claim 5 should read:
“…which is present as a salt, wherein the salt form is one of the following structures:
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or
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.”
To maintain proper grammar, claim 7 should read:
“A crystalline form according to claim 5, which is characterized by…”
The instant claims should be written in singular form. Therefore, claim 15 should read:
“…further including a step of deuteration to obtain the deuterated analog[[s]] of the solid compound[[s]] and salt[[s]], wherein the deuterated analog[[s]] is one of the following structures…”
Appropriate correction is required.
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
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
A method for treatment of a herpes simplex infection or -mediated disorder, comprising administering the pharmaceutical composition according to claim 11 to a patient in need thereof;
does not reasonably provide enablement for:
A method for prophylaxis of a herpes simplex infection or -mediated disorder, comprising administering the pharmaceutical composition according to claim 11 to a patient in need thereof.
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/or use 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 solid crystalline forms of compounds useful as helicase-primase inhibitors, compositions thereof, methods of producing the same, and methods of using the same in the treatment of herpes simplex infection and -mediated diseases.
State of the prior art and the predictability or lack thereof in the art
Prior art referenced:
Colditz et al. (Colditz) (Colditz, G. A. et al. Prevention Trials: Their Place in How We Understand the Value of Prevention Strategies. Annu. Rev. Public Health 2010, 31, 105-120.)
According to Colditz, treatment trials generally involve motivated patients with an existing disease, relatively high treatment adherence, and outcomes that can be assessed over a shorter time period. Prevention trials, on the other hand, often require large numbers of healthy participants to be followed for many years, during which substantial nonadherence can complicate or bias the assessment of preventive efficacy (see pg. 113, the four sentences right before the “Time Frame of Disease Process” section).
Accordingly, the outcome of disease-prevention studies is comparatively difficult to predict and establish reliably. Evidence that an intervention treats an existing disease does not necessarily demonstrate that it will prevent the disease, particularly where prolonged follow-up and declining adherence can obscure or underestimate any actual preventative effect.
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/preventive efficacy of compounds.
The breadth of the claims
Claim 12 is broad insofar as it encompasses both prophylaxis and treatment of any herpes simplex infection or herpes simplex-mediated disorder using the pharmaceutical composition of claim 11. The claim is not limited to a particular herpes-simplex virus type or preventive/therapeutic endpoint, and therefore covers a wide range of clinically and biologically distinct uses.
The presence or absence of working examples
The prior art reports treatment of herpes simplex infection in a subject using a compound encompassed by the instant invention (see WO2019068817A1, pg. 57, lines 9-21) and the instant specification provides working examples concerning the preparation and bioavailability of certain crystalline forms of compounds represented by instant Formula (I). However, the instant specification does not provide any working examples demonstrating prophylaxis of a herpes simplex infection or herpes simplex-mediated disorder using the claimed crystalline forms.
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 instant specification provides guidance regarding the preparation and characterization of certain crystalline forms of a compound according to instant Formula (I) and their use in pharmaceutical compositions. The prior art reports treatment of herpes simplex infection in a subject using a compound encompassed by the instant invention (see WO2019068817A1, pg. 57, lines 9-21; note: the crystallinity of that compound is unidentified) while the instant specification provides working examples concerning the bioavailability of certain crystalline forms of compounds represented by instant Formula (I).
The specification provides no direction concerning how the claimed compositions should be administered to prevent a herpes simplex infection or herpes simplex-mediated disorder. In particular, the specification does not identify an appropriate prophylactic patient population, dosing regimen, timing or duration of administration, or measurable endpoint for determining successful prophylaxis.
Accordingly, a POSITA would require substantial experimentation to determine whether, and under what conditions, the claimed crystalline forms provide prophylactic efficacy across the full scope of claim 12. Such experimentation would likely require selection of appropriate patient populations and preventive endpoints, optimization of dosing and administration schedules, and prolonged studies involving large numbers of uninfected or at-risk subjects. In view of the limited guidance provided and the breadth and unpredictability of the claimed prophylactic use, the required experimentation would be more than routine.
Written Description
Claims 1-15 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.
Part 1:
The instant specification does not define the term “co-crystal.” Therefore, Examiner referred to the definition provided by the FDA (see the glossary on pg. 4 of the pdf titled “Regulatory Classification of Pharmaceutical Co-Crystals Guidance for Industry”). According to the FDA:
Co-crystals: Crystalline materials composed of two or more different molecules, one of which is the API [i.e., Active Pharmaceutical Ingredient], in a defined stoichiometric ratio within the same crystal lattice that are associated by nonionic and noncovalent bonds.
These different molecules that are within the crystal lattice are referred to as “coformers” (see pg. 2, section “III. Discussion”, 1st paragraph, last sentence).
Coformer: A component that interacts nonionically with the API in the crystal lattice, that is not a solvent (including water), and is typically nonvolatile.
Claim 1 encompasses a co-crystal of a compound according to Formula (I) and claim 13 encompasses a process for preparing a co-crystal of the IM-250 compound (i.e., a species of instant Formula (I)). The specification, however, does not:
identify any coformer that successfully forms a co-crystal with a compound of Formula (I),
disclose any representative co-crystal species,
provide an example or method of preparing such a co-crystal, or
describe structural or other identifying characteristics that would allow a POSITA to recognize which compound-coformer combinations fall within the claimed genus.
According to the prior art:
“[C]oformer selection is one of the main challenge[s] in cocrystal development which is compatible with API. A general approach to coformer selection is by “tactless” cocrystal screening, whereby a predetermined library of pharmaceutically acceptable/approved compounds is used to attempt cocrystallization. In cocrystal development one of the approach[es] of coformer selection is based on trial and error. Other approaches are supramolecular synthon approach which utilizes Cambridge Structural Database (CSD) to effectively prioritize coformers for crystal form screening, Hansen solubility parameter and knowledge of hydrogen bonding between coformer and API.”
See abstract of Fukte, S. R. et al. Coformer selection: an important tool in cocrystal formation. Int J Pharm Pharm Sci 2014, 6, 9-14.)
Although co-crystal screening and trial-and-error testing is a method known in the art, the ability of a POSITA to conduct a screening program and potentially discover a suitable co-crystal does not establish that Applicant possessed the claimed genus as of the filing date.
Further, according to 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 provides neither representative co-crystal species nor a disclosed or art-recognized correlation permitting a POSITA to identify successful coformers. Accordingly, the generic recitation to a “co-crystal” describes a result to be sought rather than subject matter shown to have been possessed.
This rejection can be overcome by amending the claims to delete the recitation of “co-crystal.”
Claims 2-12 and 14-15, which are dependent on claims 1 or 13, are also rejected for further requiring and/or reciting “co-crystal” which does not have written description support.
Part 2:
Claim 1 broadly recites “a crystalline form of a compound according to Formula (I)” without limiting the crystalline form by XRPD peaks or any other identifying characteristics. The claim therefore encompasses the full genus of crystalline forms of a compound according to Formula (I), including crystalline species having XRPD patterns that may not overlap at all with the XRPD patterns of the crystalline species disclosed in the instant specification.
Although the specification discloses certain specific crystalline forms, it does not provide a representative number of crystalline species reflecting the full variety/scope of the claimed genus. A POSITA would further understand that different solvents, temperatures, cooling rates, seeding conditions, and other crystallization parameters may produce different crystalline forms. Therefore, disclosure of conditions for preparing only a limited number of forms does not adequately represent the full genus encompassed by the claim. Accordingly, the disclosure does not reasonably convey that Applicant possessed the full scope of the claimed genus as of the effective filing date.
Claims 2, 3, 5, 6, 11, and 12, which are dependent on claim 1, are further rejected for requiring and/or reciting elements that do not have written description support.
Part 3:
Claim 12 encompasses a method for prophylaxis of a herpes simplex infection or -mediated disorder, comprising administering the pharmaceutical composition according to claim 11 to a patient in need thereof. The specification, however, does not disclose any working examples that:
demonstrate prophylactic efficacy,
identify a particular herpes simplex infection or herpes simplex-mediated disorder that was successfully prevented, or
provide dosing, timing, patient-selection, duration-of-administration, or endpoint information showing that the inventors possessed a prophylactic method within the scope of the claim.
The disclosed preparation, characterization, and bioavailability studies concerning the crystalline forms, together with prior-art evidence of treatment of an established herpes-simplex infection (see WO2019068817A1, pg. 57, lines 9-21), do not demonstrate possession of the distinct use of administering the claimed compositions to prevent an infection or disorder before it occurs.
Although a POSITA may have been capable of conducting prevention studies, the ability to perform prolonged experimentation and potentially determine whether prophylaxis is effective does not establish that Applicant possessed the claimed prophylactic methods as of the effective filing date. This is particularly true where prevention trials may require many years of follow-up and may be complicated by substantial nonadherence to the preventative therapy, which can obscure or bias the observed preventive effect (see the Colditz reference cited in the “2. State of the prior art and the predictability or lack thereof in the art” subsection of the “Scope of Enablement” section above for details). In the absence of prophylactic examples, supporting data, or meaningful guidance addressing these uncertainties, the specification does not reasonably convey possession of the full scope of the prophylaxis limitation recited in claim 12.
Part 4:
Since claim 15 is dependent on claim 13, claim 15 requires performing the process of claim 13 through intermediates P2b, P2c, and P2d to obtain IM-250, and further requires a deuteration step to yield one of the specified deuterated solid compounds recited in claim 15. The specification, however, does not describe deuterating IM-250 prepared through the process of claim 13, followed by adding a deuteration step to that process to obtain the recited deuterated products.
Rather, the specification prepares the deuterated compounds through a separate synthetic pathway in which deuterium is introduced in the first step and the synthesis proceeds through intermediates 9a, 9b, 9c, 9d, 9e, 9f, 9g, and 9h (see instant specification, pg. 47-50) instead of the P2b, P2c, and P2d sequence required by claim 13. Disclosure of this alternative route does not reasonably convey that Applicant possessed the particular combined process recited in claim 15. In other words, the specification does not reasonably convey possession of a process of claim 13 in combination with a subsequent deuteration step that selectively replaces only the three hydrogen atoms of the methyl group attached to the thiazole moiety (without deuterating other positions) to produce the specified deuterated products. The specification does not describe how such site-selective deuteration could be achieved after assembly of the complete IM-250 structure. Instead, the specification teaches introduction of the deuterated methyl group at an earlier state of the synthesis through a distinct sequence of intermediates that are different than the intermediates disclosed in claim 13.
Accordingly, the specification does not provide adequate written-description support for claim 15.
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 § 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 11 and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Kleymann et al. (Kleymann) (WO2019068817A1; published April 11, 2019).
Kleymann discloses the isolation of Example 7(+) (see pg. 36, lines 25-30):
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(which is the same as IM-250 in the instant case). Kleymann also discloses the application of Example 7(+) in treating herpes encephalitis (pg. 57, lines 9-21) by administering an intravenous dose of Example 7(+) to mice. Note: the intravenous dose of Example 7(+) is a pharmaceutical composition comprising Example 7(+) (i.e., IM-250 in the instant case) dissolved in DMSO in heterologous plasma (pg. 57, lines 11-13).
Kleymann does not state whether Example 7(+) was crystalline or not. However, regardless of the solid-state form of Example 7(+), once a crystalline form of a compound is fully dissolved in a liquid carrier such as liquid excipients which include DMSO, the resulting solution no longer retains any crystalline structure and is indistinguishable from a solution prepared from Example 7(+) of another crystalline form or even Example 7(+) in amorphous form. Therefore, Kleymann disclosing a pharmaceutical composition comprising Example 7(+) dissolved in DMSO and being used to treat a herpes simplex infection reads on instant claims 11 and 12.
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.
Rejection Part 1:
Claims 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over:
Kleymann et al. (Kleymann) (WO2019068817A1; published April 11, 2019).
Regarding claim 13:
Kleymann discloses the isolation of Example 7(+) (see pg. 36, lines 25-30):
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(which corresponds to IM-250 and falls within the scope of compounds recited in the instant claims). Kleymann also teaches a synthetic route for preparing a racemic mixture containing Example 7(+) and its corresponding enantiomer. The general synthetic pathway of Kleymann and the pathway of instant claim 13 are compared below:
#
Kleymann (pg. 33-35)
Instant claim 13
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IM-250
Pathway similarities: The conversion from 6 [Wingdings font/0xE0] 7 (as disclosed by Kleymann) is the same as the conversion from P2d [Wingdings font/0xE0] IM-250 (as disclosed in instant claim 13).
Pathway differences: (1) The pathway in instant claim 13 uses a thiazole starting material that is bonded to a -S(O)CH3 substituent whereas the pathway disclosed by Kleymann uses a thiazole starting material that is bonded to a -SCH3 substituent. (2) The pathway disclosed by Kleymann produces a racemic mixture whereas the pathway recited in instant claim 13 yields in an enantiopure product.
Even though the pathway disclosed by Kleymann differs from the process recited in instant claim 13, a POSITA would have found it prima facie obvious, before the effective filing date of the claimed invention, to modify Kleymann’s pathway by applying known reactions and synthetic techniques taught in the prior art. After all, Kleymann explicitly teaches: “homochiral compounds of the present invention may be prepared by stereoselective syntheses, giving rise to enantioenriched final compounds which may be recrystallized to afford enantiopure homochiral compounds” (pg. 31, lines 25-27). “Syntheses of optically active sulfoximines is also possible from optically active sulfoxides. The review Chem. Lett.2004:33,482 summarizes routes for synthesis of sulfoximines. A recent publication in Angew. Chem. Int. Ed.2016:55,7203 summarizes state of the art of synthesis of sulfoximines” (pg. 32, lines 1-5).
Therefore, a POSITA would have found it obvious to use
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(disclosed in instant claim 13) as the starting material instead of
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(as disclosed in Kleymann) because Kleymann explicitly states: “[s]yntheses of optically active sulfoximines is also possible from optically active sulfoxides” (pg. 32, line 2).
A POSITA would have also found it obvious to react instant intermediate P2c with Rh2(OAc)4, tert-butyl carbamate, magnesium oxide, and (diacetoxy)iodobenzene to form P2d (which corresponds to compound 6 in the pathway disclosed by Kleymann). A POSITA would have found it obvious to use those specific reagents because Kleymann explicitly teaches: “The review Chem. Lett.2004:33,482 summarizes routes for synthesis of sulfoximines” (pg. 32, line 3). Within the Chem. Lett. reference cited by Kleymann, it explicitly teaches how to transform a sulfoxide into a sulfoximine:
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(see scheme 12 of Chem. Lett. reference; Note: the reagents used are the same as those listed in instant claim 13 to convert P2c to P2d).
A POSITA would have been motivated to modify Kleymann’s synthetic pathway to arrive at the process recited in claim 13 because the modified pathway (i.e., the process of claim 13) provides a homochiral, enantiopure product rather than the racemic mixture produced by Kleymann’s disclosed route. Therefore, instant claim 13 is rendered obvious.
Regarding claim 14:
Kleymann teaches that compounds containing “one or more basic groups, i.e. groups which can be protonated [such as the instant compounds], can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride… [and] naphthalenedisulfonic acids…” (pg. 10, lines 23-28). Kleymann further teaches that such salts may be prepared by customary methods known to a person of ordinary skill in the art (pg. 11, lines 4-7). Therefore, following preparation of IM-250 according to the obvious process of instant claim 13, a POSITA would have been motivated to deprotect intermediate P2d using hydrochloric acid or naphthalenedisulfonic acid and thereby obtain the IM-250 HCl or napadisylate salt because both hydrochloric acid and naphthalenedisulfonic acid would remove the acid-labile protecting group and provide the pharmaceutically acceptable acid-addition salt recited in instant claim 14. A POSITA would have had a reasonable expectation of success because acid-mediated deprotection and hydrochloride or napadisylate-salt formation were conventional reactions that are known in the art.
A POSITA would have been further motivated to prepare the hydrochloride salt form of IM-250 because:
chloride was recognized as the most frequently used anionic counterion for forming active pharmaceutical ingredient salts and
see abstract of Paulekuhn (Paulekuhn, G. S. et al. Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database. J. Med. Chem. 2007, 50, 6665-6672.)
salt formation, in general, is a well-known technique for modifying and optimizing the physicochemical properties of ionizable drug-development compounds
see Paulekuhn, introduction section, 1st sentence.
Therefore, a process of making salt forms of IM-250 (as recited in instant claim 14) is rendered obvious.
Rejection Part 2:
Claims 1-3, 5, and 6 are rejected under 35 U.S.C. 103 as being unpatentable over:
Kleymann et al. (Kleymann) (WO2019068817A1; published April 11, 2019).
Kleymann discloses the isolation of Example 7(+) (see pg. 36, lines 25-30):
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(which corresponds to IM-250 and falls within the scope of compounds recited in claims 1-3, 5, and 6). Kleymann further teaches: “homochiral compounds of the present invention may be prepared by stereoselective syntheses, giving rise to enantioenriched final compounds which may be recrystallized to afford enantiopure homochiral compounds” (pg. 31, lines 25-27). A POSITA therefore would have been motivated to recrystallize Example 7(+) (or its salt form which is obvious to make as discussed in “Rejection Part 1” above ) for the stated purpose of improving enantiomeric purity and would have had a reasonable expectation of obtaining a crystalline form by applying routine recrystallization techniques known in the art (Tung, H.-H. et al. Crystallization of Organic Compounds: An Industrial Perspective; John Wiley & Sons Inc., 2009.). Although the specific crystalline form produced may not have been predictable, claims 1-3, 5, and 6 do not require any specific XRPD pattern, unit cell, or other crystalline-defining characteristic for IM-250. Accordingly, because claims 1-3, 5, and 6 encompass any crystalline form of IM-250 (or its pharmaceutically acceptable salt form), any crystalline form resulting from the application of known recrystallization techniques would fall within the scope of the claims. Therefore, claims 1-3, 5, and 6 are rendered obvious.
Rejection Part 3:
Claims 11 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over:
Kleymann et al. (Kleymann) (WO2019068817A1; published April 11, 2019).
Kleymann teaches administering a pharmaceutical composition comprising IM-250 and a pharmaceutically acceptable excipient to a subject (i.e., mice) for the treatment of a herpes simplex infection (i.e., herpes encephalitis) (see the “Claim Rejections - 35 USC § 102” section above for details). Kleymann further teaches that enantiopure final compounds, including IM-250, may be recrystallized to obtain enantiopure, homochiral compounds (pg. 31, lines 25-27). Therefore, a POSITA would have been motivated to prepare a crystalline form of IM-250 using known recrystallization techniques to obtain purified IM-250. It would also have been obvious to formulate that crystalline IM-250 in Kleymann’s pharmaceutical composition and administer it for the same disclosed therapeutic purposes. A POSITA would have had a reasonable expectation of success because the crystalline form contains the same antiviral active compound disclosed by Kleymann and, absent evidence to the contrary, any crystalline form of IM-250 would have been expected to retain the therapeutic activity attributed to IM-250. Recall: claim 12 ultimately depends on claim 1 which broadly encompasses any crystalline form of a compound according to Formula (I), rather than requiring a particular crystalline form.
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 1-3, 5, 6, and 11-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over:
claims 18-39 of U.S. Patent Application No. 19/451,608 (‘608),
claims 1-15 of U.S. Patent Application No. 19/503,013 (‘013),
claims 1-20 of U.S. Patent Application No. US 10,590,094 B2 (‘094 B2),
claims 1-6 and 10-19 of U.S. Patent Application No. US 11,278/534 B2 (‘534 B2),
claims 1-10 of U.S. Patent Application No. US 12/295,945 B2 (‘945 B2),
claims 1-25 of U.S. Patent Application No. US 12,527,778 B2 (‘778 B2), and
claims 1-23 of U.S. Patent Application No. US 12,552,756 B2 (‘756 B2).
Although the claims at issue are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claims and the claim sets from the issued patents and co-pending applications.
Rejection Part (A):
Part A-1:
Claims 18-28 of ‘608 are directed to a pharmaceutical composition comprising a compound encompassed by the formula recited in claim 18, which includes IM-250. Although instant claim 11 further specifies that the compound is present in a crystalline form, the claims are not patentably distinct because the compound species encompassed by the respective claim sets overlap. A POSITA would have found it obvious to formulate a crystalline form of an overlapping compound, such as IM-250, in the pharmaceutical compositions recited in claims 18-28 of the ‘608 application, with a reasonable expectation that the compound would retain its known therapeutic activity.
Moreover, where the pharmaceutical composition is formulated as a solution, dissolution eliminates the ordered crystal lattice such that the resulting composition contains the same dissolved active compound regardless of the solid form from which it originated (i.e., crystalline or amorphous). Therefore, the recitation of “a crystalline form” in instant claim 11 does not render the claimed pharmaceutical composition patentably distinct from the pharmaceutical compositions recited in claims 18-28 of the ‘608 application.
Part A-2:
Claims 29-39 of the ‘608 application are directed to methods for treating or preventing diseases or disorders associated with herpes virus infection (which includes herpes simplex infection and herpes simplex-mediated disorders), by administering the pharmaceutical composition of claim 18 to a patient in need thereof. These claims substantially overlap with instant claim 12, which likewise recites a method of prophylaxis or treatment of a herpes simplex infection or herpes simplex-mediated disorder by administering the pharmaceutical composition of instant claim 11.
Although instant claim 12 requires administration of a composition containing a crystalline form of a compound according to instant Formula (I), the instantly claimed method is not patentably distinct form the methods recited in claims 29-39 of the ‘608 application. A POSITA would have found it obvious to administer a pharmaceutical composition containing a crystalline form of an overlapping compound, such as IM-250, for the same prophylactic or therapeutic purposes, with a reasonable expectation that the compound would retain its known antiviral activity. Moreover, where the administered pharmaceutical composition is a solution, the active compound is present in dissolved molecular form and no longer retains the crystal lattice of the starting solid. Accordingly, a solution prepared from crystalline IM-250 would be materially the same as a solution prepared from another crystalline form or amorphous form of IM-250, further demonstrating the overlap between the methods recited in instant claim 12 and claims 29-39 of the ‘608 application.
Rejection Part (B):
Part B-1:
Claims 1-13 and 15 of ‘013 is directed to a micronized, crystalline form of the IM-250 HCl salt. This is encompassed by instant claims 1-3, 5, and 6 which broadly claims any crystalline form of a compound according to instant Formula (I) which includes IM-250. Claim 14 of ‘013 encompasses a pharmaceutical composition comprising a therapeutically effective amount of a micronized, crystalline form of Formula (I), at least one pharmaceutically acceptable excipient, and optionally a further active substance effective in treating a disease or disorder associated with a viral infection. A “micronized, crystalline form” is encompassed by the broader recitation of “a crystalline form” in instant claim 11. Accordingly, instant claim 11 is not patentably distinct from the co-pending claims which encompass a composition comprising the micronized, crystalline compound and a pharmaceutically acceptable excipient.
Part B-2:
Regarding the co-pending claims additionally requiring a further antiviral active substance, the claimed composition likewise would not have been patentably distinct from instant claim 11. Instant claim 11 uses the transitional term “comprising” and therefore does not exclude the presence of an additional active substance. Moreover, because the pharmaceutical composition of the instant case is intended for treating or preventing a herpes simplex viral infection, a POSITA would have found it obvious to include an additional antiviral agent effective against the same viral infection to provide an additional or complementary antiviral effect. A POSITA would have had a reasonable expectation that the additional antiviral agent would retain its known antiviral activity when included in the composition, absent evidence of incompatibility or an unexpected result arising from the combination.
Rejection Part (C):
Claims 1-8 and 15-19 of ‘094 B2 are directed to compounds that encompass the compounds according to instant Formula (I). Although claims 1-8 and 15-19 of ‘094 B2 do not specify the compounds to be crystalline, they are not patentably distinct from:
instant claims 1-3, 5, and 6 for reasons similar to those discussed in the “Claim Rejections - 35 USC § 103 – Rejection Part 2” section above.
Although claims 10-13 and 20 of ‘094 B2 and instant claim 12 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Part A-2 above.
Although claims 9 and 14 of ‘094 B2 and instant claim 11 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Parts A-1 and B-2 above.
Rejection Part (D):
Claims 1-6 of ‘534 B2 are directed to compounds that encompass the compounds according to instant Formula (I). Although claims 1-6 of ‘534 B2 do not specify the compounds to be crystalline, they are not patentably distinct from:
instant claims 1-3, 5, and 6 for reasons similar to those discussed in the “Claim Rejections - 35 USC § 103 – Rejection Part 2” section above.
Although claims 10-19 of ‘534 B2 and instant claim 12 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Part A-2 above.
Rejection Part (E):
Claims 1-6 of ‘945 B2 are directed to compounds that encompass the compounds according to instant Formula (I). Although claims 1-6 of ‘945 B2 do not specify the compounds to be crystalline, they are not patentably distinct from:
instant claims 1-3, 5, and 6 for reasons similar to those discussed in the “Claim Rejections - 35 USC § 103 – Rejection Part 2” section above.
Although claim 7 of ‘945 B2 and instant claim 11 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Part B-2 above.
Although claims 8-10 of ‘945 B2 and instant claim 12 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claim from the issued patent, for reasons similar to those discussed in the rejection set forth in Part A-2 above.
Rejection Part (F):
Claims 1-11 of ‘778 B2 are directed to compounds that encompass the compounds according to instant Formula (I). Although claims 1-11 of ‘778 B2 do not specify the compounds to be crystalline, they are not patentably distinct from:
instant claims 1-3, 5, and 6 for reasons similar to those discussed in the “Claim Rejections - 35 USC § 103 – Rejection Part 2” section above.
Although claim 12 of ‘778 B2 and instant claim 11 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Part B-2 above.
Although claims 13-25 of ‘778 B2 and instant claim 12 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claim from the issued patent, for reasons similar to those discussed in the rejection set forth in Part A-2 above.
Rejection Part (G):
Claims 1-11 of ‘756 B2 are directed to compounds that encompass the compounds according to instant Formula (I). Although claims 1-11 of ‘756 B2 do not specify the compounds to be crystalline, they are not patentably distinct from:
instant claims 1-3, 5, and 6 for reasons similar to those discussed in the “Claim Rejections - 35 USC § 103 – Rejection Part 2” section above.
Although claim 12, 13, 19, and 20 of ‘756 B2 and instant claim 11 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claims from the issued patent, for reasons similar to those discussed in the rejection set forth in Parts A-1 and B-2 above.
Although claims 14-18 and 21-23 of ‘756 B2 and instant claim 12 are not identical, they are not patentably distinct from each other because there is significant overlap between the instant claim and the claim from the issued patent, for reasons similar to those discussed in the rejection set forth in Part A-2 above.
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.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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