DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of Group I, with the addition of crystalline From I as the crystalline Form species, and HIV protease inhibitors as the additional therapeutic agent species in the reply filed on 08/03/2026 is acknowledged.
Claims 8, 18-21, 56-59, and 70 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 08/03/2026.
Priority
This application claims the benefit of U.S. Provisional Application No. 63/505,226, filed on May 31, 2023.
Specification
The disclosure is objected to because of the following informalities: the intended scope and purpose of the incorporation by reference of U.S. Application No. 18/061,375 is unclear. Paragraph [0075] identifies the presently depicted structure as Compound 1 and immediately thereafter states “see e.g., U.S. Application No. 18/061,375, the disclosure of which is incorporated herein by reference in its entirety.” Review of U.S. Application No. 18/061,375 has not identified therein the complete Compound 1 presently depicted in the instant specification or a synthesis thereof. Accordingly, it is unclear whether Applicant intends the incorporated application merely to provide related or background disclosure or intends to rely upon the incorporated application for disclosure concerning the identity or preparation of Compound 1. Applicant is required to clarify the purpose and scope of the incorporation by reference.
To the extent Applicant intends to rely upon U.S. Application No. 18/061,375 to supply material necessary to satisfy the requirement of 35 U.S.C. 112(a), Applicant’s attention is directed to 37 CFR 1.57(d) and MPEP §608.01(p), which provide that essential material may be incorporated by reference only to a U.S. patent or U.S. patent application publication.
Appropriate correction is required.
Claim Status
Claims 1-8, 18-21, 51-53, 56-59, and 71 are pending. Claims 9-17, 22-50, 54-55, and 60-70 are canceled. Claims 8, 18-21, 56-59, and 70 are withdrawn. Claims 1-7 and 51-53 are examined in accordance with the elected species.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/19/2024 and 08/03/2026 has been considered by the examiner.
Claim Objections
Claim 6 is objected to because of the following informalities: the recitation “characterized by a DSC thermogram having a melting onset at about 202oC” follows a parent claim that already characterizes the crystalline form I by XRPD. For clarity and to make clear that the DSC limitation constitutes an additional characterization of the crystalline form rather than an alternative characterization, claim 6 should be amended to recite, for example, “further characterized by a DSC thermogram having a melting onset at about 202oC,”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 51-53 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 to the extent that the claims encompass solid pharmaceutical compositions comprising a specifically disclosed crystalline Form of Compound 1 and pharmaceutically acceptable excipients under formulation under formulation and processing conditions that do not materially alter the disclosed crystalline form, does not reasonably provide enablement for full scope of the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 51 is directed to pharmaceutical composition comprising a therapeutically effective amount of a crystalline form of claim 1, and a pharmaceutically acceptable excipient. Claim 1, from which claim 51 ultimately derives its crystalline-form limitation, broadly encompasses a crystalline form of Compound 1 without restricting the crystalline material to a particular form, XRPD pattern, DSC thermogram, formulation, excipient, amount or set of formulation conditions.
Claim 52 and 53 further broaden the pharmaceutical composition embodiments by permitting the composition to contain, one, two, three, or four additional therapeutic agents, with claim 53 encompassing numerous chemically and therapeutically diverse classes of additional agents.
The specification demonstrates that Compound 1 is capable of existing in multiple solid-state forms and that the solid-state form obtained is dependent upon the conditions under which Compound 1 is processed. For example, the specification identifies crystalline Forms I, II, and III and further describes various solvated forms of Compound 1. The specification additionally demonstrates preparation of different forms using different solvents and processing conditions. Thus, Applicant’s own disclosure establishes that the solid-state structure of Compound 1 is sensitive to its physiochemical environment and processing history.
The specification provides general disclosure concerning pharmaceutical compositions and identifies numerous pharmaceutically acceptable excipients and conventional dosage forms. (SEE ¶¶ [0310]-[0313] and [0325]-[0337]. The specification additionally provides broad dosage and administration teachings at ¶¶ [0357]-[0365[. However, these teachings do not provide representative experimental pharmaceutical formulations demonstrating that the claimed crystalline form is maintained when combined across the full scope of pharmaceutically acceptable excipients encompassed by claim 51, much less when further combined with the one to four additional therapeutic agents encompassed by claims 52 and 53. The concern is supported by the state of the pharmaceutical solid-state art. Sood et al. (Ther Deliv. 2014 Oct;5(10):1123-42) teaches that excipients and formulation variablesd are used to modify stability and physiochemical properties of dosage forms and importantly, that excipients may influence the crystal structure of solid and may modify the rate and direction of crystal growth. Thus, the effect of incorporating a crystalline active pharmaceutical ingredient into a formulation is not necessarily neutral. Sood et al. further teaches that crystal habit may influence pharmacokinetic properties of a dosage form. (See Abstract.)
Censi et al. (Molecules 2015, 20, 18759-18776) similarly teaches that crystalline polymorphs having the same chemical composition possess different internal crystal structures and, consequently, can possess different physiochemical properties because of their different lattice structures and/or molecular conformations. Censi et al. further teaches that polymorphic forms may differ in properties including melting point, density, stability, and solubility, and that particular excipients and technological processes may promote solid-state transitions. Censi et al. additionally explains that solid-state transformation must be monitored during formulation, manufacture and storage to ensure reproducible pharmaceutical performance. (See § 3, p. 18762-18763).
The teachings of Sood and Censi are relied upon not to establish that every pharmaceutically acceptable excipient necessarily converts Compound 1 into a different crystalline form, but rather as evidence that the effect of excipients and formulation condition upon crystalline form cannot reasonably be presumed to be invariant across the broad scope encompassed by the claims. Accordingly, while the specification enables preparation and characterization of particular crystalline forms of Compound 1 and generally teaches that those materials may be formulated into pharmaceutical compositions, the disclosure does not provide sufficient representative examples, formulation-specific solid-state characterization, or a generally applicable technical principle by which a person of ordinary skill could determine, without undue experimentation, which of the numerous excipients, excipient concentrations, processing conditions, dosage forms, and additional therapeutic agents encompassed by claims 51-53 would preserve the requisite crystalline material throughout preparation of the claimed pharmaceutical composition.
The factors set forth in Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), are considered as follows.
Breadth of claims.
The claims are broad relative to the enabling disclosure. Claim 51 is not restricted to a
Particular excipient or class of excipients, amount of excipients, dosage form, manufacturing process, or formulation condition. It therefore encompasses pharmaceutical composition employing essentially any pharmaceutically acceptable excipient compatible with the claim language. Claims 52 and 53 further encompass compositions containing as many as four additional therapeutic agents selected from numerous structurally and mechanistically diverse therapeutic classes. The breadth of possible combination of crystalline form, excipient(s), excipient amount(s), processing conditions and additional therapeutic agent(s) is therefore substantial.
Nature of the invention.
The claimed subject matter concerns pharmaceutical compositions containing a
polymorphic crystalline active pharmaceutically active ingredient. Applicant’s own specification establishes that Compound 1 exhibits solid-state polymorphism and solvate formation and that different processing and solvent conditions produce different solid-state forms. Thus, preservation of the crystalline material within a pharmaceutical composition concerns solid-state interactions and formulation conditions rather than merely mixing an invariant molecular species with an inert carrier.
State of the art.
The prior art establishes that polymorphism and solid-state transformation are
recognized concerns in pharmaceutical development. Sood et al. teaches that excipients and formulation variables can influence crystal structure and crystal growth. Censi et al. teaches that different physiochemical properties and that excipients and technological processes can influence solid-state transitions. Accordingly, the state of the art establishes that formulation components cannot universally be presumed to have no effect upon the crystalline state of an active pharmaceutical ingredient.
Level of ordinary skill in the art.
A person of ordinary skill would have possessed substantial knowledge concerning
pharmaceutical formulation, polymorphism, crystallization, and conventional analytical techniques such as XRPD and DSC. This factor weighs in Applicant’s favor to the extent that the skilled artisan would have known how to formulate and characterize individual compositions. However, a high level of skill does not provide a predictive teaching identifying which members of the broad universe of excipients and additional therapeutic agents encompassed by claims 51-53 will preserve a particular crystalline lattice under the numerous processing and storage conditions encompassed by the claims. Rather, the skilled artisan’s knowledge provides the means for experimentally determining the resulting solid-state.
Predictability and unpredictability of the art.
Although persons of ordinary skill possessed conventional methods for preparing
pharmaceutical formulations and characterizing solid-state forms, the evidence does not establish that the effect of the broad range of excipient, excipient concentrations, processing conditions, dosage forms, and additional therapeutic agents encompassed by claims 51-53 on the crystalline state of Compound 1 could reliably extrapolated across the full scope of the claims. Applicant’s own specification demonstrates that the identical Compound 1 can assume multiple crystalline and solvated forms depending upon its physiochemical environment and processing conditions. Consequently, Sood et al. teaches that excipients may influence crystal structure and crystal growth behavior, while Censi et al teaches that different crystalline forms may exhibit material different physiochemical and pharmaceutical properties and that formulation components and technological processes may facilitate solid-state transitions. Thus, although individual formulations could be prepared and evaluated using routine techniques, the specification does not provide a generally applicable predictive principle permitting the skilled artisan to identify operative embodiments throughout the full breadth claimed without the need for substantial empirical formulation and solid-state characterization.
Amount of guidance or direction provided in the specification.
The specification provides substantial general guidance regarding pharmaceutical
dosage forms, routes of admiration, excipients and dosage ranges. However, the specification does not provide corresponding guidance identifying which excipients or classes thereof preserve the claimed crystalline material; which excipients or processing condition induce conversation to another polymorph, solvate, hydrate or amorphous material; permissible concentrations of the respective excipients for preservation of the crystalline state; or a general predictive relationship between excipient identity and maintenance of the claimed crystalline lattice. Likewise, the specification does not provide such guidance for numerous additional therapeutic agents encompassed by claims 52 and 53.
Thus, although the specification teaches the skilled artisan numerous materials that may be selected, it does not provide sufficient direction concerning which selections will produce pharmaceutical compositions retaining the crystalline subject matter required by the claims.
Existence of working examples.
The specification contains working examples concerning preparation and solid-state
characterization of particular forms of Compound 1. Those examples establish enablement of at least those particular crystalline materials and closely corresponding embodiments. However, no representative working pharmaceutical-composition examples have been identified demonstrating retention of the claimed crystalline material across the broad range of excipients, dosage forms, and additional therapeutic agents encompassed by claims 51-53. The rejection therefore does not take the position that Applicant has enabled no embodiment. Rather, the concern is that the demonstrated embodiments and general formulation disclosure are not reasonably commensurate with the substantially broader claimed scope.
Quantity of experimentation necessary.
To practice the full scope of claims 51-53 while ensuring that the composition contains
the required crystalline for, a person of ordinary skill would have to select among the numerous encompassed excipients, excipient concentrations, formulation processes and, for claims 52-53, additional therapeutic agents; prepare the respective compositions; and determine experimentally whether the crystalline state of Compound 1 is retained or transformed. Such determination would reasonably require solid-state characterization, e.g., XRPD, DSC, and/or other appropriate analytical testing across material different formulations and processing conditions. Although each individual characterization technique may itself have been conventional, the issue is not whether XPRD and DSC was difficult to perform. Rather, the issue is the extent of empirical formulation and characterization required to identify operative embodiments throughout the broad scope claims 51-53 in the absence of a disclosed predictive principle identifying which formulation conditions preserve the claimed crystalline state. The necessity to proceed through the claimed scope by formulation, testing and solid-state characterization weighs toward undue experimentation.
Conclusion
Upon consideration of Wand factors as a whole, the breadth of claims 51-53, the polymorphic nature of Compound 1 demonstrated by Applicant’s own specification, the recognized ability of excipients and formulation variables to influence crystal structure and solid-state transitions, the absence of representative pharmaceutical-composition examples reasonably commensurate with the breadth claimed, and the quantity of empirical formulation and the solid-state characterization required to establish that the specification does not enable the full scope of clams 51-53 without undue experimentation.
The Examiner acknowledged that the specification enables preparation of the specifically disclosed crystalline forms of Compound 1 and provides sufficient general teachings to prepare at least certain pharmaceutical compositions containing such crystalline material. The rejection is therefore not based upon an assertion that the pharmaceutic compositions containing Compound 1 cannot be made. Rather, the rejection is directed to the substantial broader scope of claims 51-53, which encompass the claimed crystalline material in combination with broadly unrestricted pharmaceutical acceptable excipients and, in claims 53-53, up to four additional therapeutic agents, without disclosure reasonably enabling preservation and use of the claimed crystalline state throughout that scope without undue experimentation.
Accordingly, claims 51-53 are not enabled commensurate in scope with the subject matter presently claims and are rejected under 35 U.S.C. 1121(a).
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2 and 3 are indefinite because the recitations “crystalline Form I,” crystalline Form II,” and “crystalline Form III” do not provide sufficiently defined boundaries by which a person of ordinary skill in the art can determine whether a particular crystalline sample falls within the claimed form.
Claim 2 recites that the crystalline form of claim 1 is selected from crystalline Forms I, II, and III, while claim 3 recites that the crystalline form is crystalline form I. The claims themselves do not identify the structural or analytical criterion necessary and sufficient assigning a crystalline material to any of the recited forms. The specification explains at ¶ [0083] that different crystalline and solvate forms may be identified using solid-state characterization methods such as XRPD, and that DSC may further assist in identifying the form. However, the specification provides numerous potentially relevant characteristics for the disclosed forms without identifying which characteristics or combination thereof establishes the boundary of the terms “Form I,” “Form II,” and “Form III.” For example, Form I is characterized by an extensive XRPD pattern and peak listing ¶ [0484], Table 1-A and Fig. 4), a DSC melting onset of about 202oC (¶ [0485] and Fig. 5), and additional TGA and DVS characteristics. Forms II and III are likewise characterized by different XRPD and thermal data. Moreover, the disclosed forms exhibit overlapping or closely positioned XRPD reflections. By way of example, Form I includes reflections at approximately 6.6o, 8.7o, and 12.6o 2-Theta, Form II includes reflections at approximately 6.5o, 8.9o, and 12.8o, and Form II includes reflections at approximately 6.5o, 8.9o, and 12.8o. The specification additionally acknowledges at ¶ [0491] that materials having slight differences in crystal lattice parameters may nevertheless exhibit similar XRPD peak positions and both be designated Form II.
Accordingly, it is unclear whether classification as Form I, Form II, and Form III requires correspondence with the complete XRPD pattern, a particular subset of XRPD peaks, lattice parameters, DSC characteristics, preparation conditions, or some combination thereof. The specification therefore does not provide an objective criterion by which a person of ordinary skill in the art can determine with reasonable certainty the boundaries of the crystalline-form terminology recited in claims 2 and 3.
Claim 4 is further indefinite because the claim recites that crystalline Form I has “at least three XRPD peaks” selected from 6.2o, 6.6o, 8.7o, 10.5o, 12.4o, 12.6o, 13.8o, 23.1o, and 25.7o 2-Theta ± 0.2o, but does not identify which three peaks, or which combination of peaks, is necessary and sufficient to characterize the claimed crystalline Form I.
The claim therefore encompasses any combination of at least three of the nine recited reflections. In contrast, the experimentally prepared Form I is characterized in ¶ [0484], Table 1-A and Fig. 4 by a substantially more extensive XRPD fingerprint containing numerous additional reflections.
The specification does not establish that every permitted combination of three of the nine recited peaks uniquely identifies Form I or distinguishes Form I from other crystalline forms, solvates, hydrates, mixtures, or other solid-state forms of Compound 1. Insteadd, the specification demonstrates that different crystalline forms of Compound 1 may exhibit overlapping or closely positioned XRPD reflections.
Accordingly, it is unclear whether a crystalline sample exhibiting any arbitrary three of the recited reflections but otherwise possessing an XRPD pattern materially different from the disclosed Form I pattern, constitutes “crystalline Form I” with the scope of claim 4. A person of ordinary skill in the art therefore would not be reasonably apprised of the metes and bounds of the claim.
Claim 5 is indefinite because the recitation that Form I is characterized by an XRPD pattern “substantially as shown in Fig. 4” fails to establish an objective standard for determining the degree of correspondence required between an experimentally obtained XRPD pattern and Fig. 4.
Neither the claim nor the specification identifies which characteristics of Fig. 4 must be retained, or the permissible degree of variation therein, for a pattern to remain “substantially” as shown. For example, it is unclear whether substantial correspondence requires the presence of all principal reflections, only selected reflections, correspondence in relative peak intensities, absence of additional reflections, or some combination thereof. Although the specification provides a 0.2o 2-Theta tolerance in connection with certain individually recited XRPD peaks, the tolerance does not establish the permissible variation in the overall XRPD pattern encompassed by the phrase “substantially as shown in Fig. 4.” Therefore, the specification does not provide an objective boundary separating XRPD patterns that are substantially as shown in Fig. 4 from those that are not. Terms of degrees aren’t per se indefinite; the relevant question is whether the specification supplies an objective standard. MPEP § 2173.05 expressly applies that analysis.
Claim 6 depends from claim 3 and recites that crystalline Form 1 is “characterized by a DSC thermogram having a melting onset at about 202oC.” Claim 6 does not require the XRPD pattern, characteristic XRPD reflections, unit-cell parameters, or another structural characteristic that identifies the particular crystal lattice designated as crystalline Form I.
The specification demonstrates that DSC melting onset alone does not uniquely distinguish the disclosed crystalline forms of Compound 1. In particular, the specification reports a DSC melting onset of about 202oC for crystalline Form 1, while crystalline Form II exhibits a DSC melting onset of about 201oC, notwithstanding that Forms I and II are separately identified crystalline forms having different solid-state structure and XRPD characteristics.
Accordingly, it is unclear whether a crystalline material of Compound 1 exhibiting a DSC melting onset at or near 202oC but having a crystal lattice or XRPD pattern different from the disclosed Form I, satisfies the limitation “crystalline Form I” as characterized in claim 6. The claim does not provide an objective criterion sufficient to distinguish the claimed Form I from another crystalline Form exhibiting the same or substantially similar thermal behavior. Therefore, a person of ordinary skill in the art would not be reasonably apprised of the metes and bounds of claim 6. The same principle applies to claims 5 and 7.
Claim 7 is indefinite because the recitation that Form I is characterized by a DSC thermogram “Substantially as shown in Fig. 5” does not establish an objective standard for determining the degree of correspondence required between a measured DSC thermogram and Fig. 5.
Fig. 5 contains multiple independently measurable characteristics, including an onset at approximately 202.07oC, a peak at approximately 206.53oC, an enthalpy of approximately 21.82 J/g, the shape of endothermic event, and additional thermal behavior at higher temperatures. Neither the claim nor the specification identifies which of these characteristics must correspond to Fig. 5, or the degree of permissible variation in such characteristics, for a thermogram to be considered “substantially as shown.” Accordingly, a person of ordinary skill in the art would not be reasonably apprised of the boundary between DSC thermogram falling within and outside the scope of claim 7.
Claim Interpretation
The following prior-art rejections are made in accordance with the principles of compact prosecution notwithstanding the rejection of claims 2-5 and 7 under 35 U.S.C. 112(b). For purpose of applying the prior art, the claims are given their broadest reasonably interpretation consistent with the specification. The specification is consulted to ascertain the meaning of the terminology employed in the claims; however, limitations disclosed only in the specification are not imported into the claims. Accordingly, claim 1 is interpreted as encompassing a crystalline Form of Compound 1 without limitation to a particular atropisomeric configuration or atropisomeric ratio. The specification expressly states at paragraph [0077] that Compound 1 has two restricted rotational axes resulting in four atropisomers. Although paragraph [0481] reports that the particular MeCN-solvate crystal subjected to SCXRD consisted of the major atropisomer at the biaryl rotational axis, claim 1 does not recite the major atropisomer, a particular configuration at either rotational axis, or a particular atropisomeric ratio. Such limitations disclosed in the specification are therefore not imported into claim 1.
claims 2 and 3 are also not interpreted as positively requiring the particular XRPD peaks, complete XRPD patterns, DSC values, lattice parameters, or other analytical characteristics that are expressly recited only in dependent claims or otherwise described in the specification. This is squarely consistent with MPEP §2111 and 2173.06 use the specification to construe the claim, but don’t rewrite the claim with limitation Applicant didn’t recite.
Claim Rejections - 35 USC § 103
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.
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.
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.
Claim(s) 1-4 and 51-53 are rejected under 35 U.S.C. 103 as being unpatentable over Farand et al. (WO2023102239A1) in view of Shi et al. (US11267799B2).
Farand discloses compounds useful for the treatment of HIV infection, including compound structurally corresponding to or closely related to Compound 1 presently claimed, and methods for their preparation, including 2-(2-(4-(A-(4-chloro-7-(2-((15)-l-(2-((3b5,4a/?)-5,5-difluoro-3- (trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrrol-l- yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l- yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)methylsulfonamido)-2-methyl-4- oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid (44). See e.g., ¶¶[0515]-0525], Example 44. Farand further teaches pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound together with one or more pharmaceutically acceptable carriers or excipients and teaches administration of such compositions of treatment of HIV infection. Farrand additionally teaches combination therapy in which the disclosed compounds are administered with one or more additional therapeutic agents, including HIV protease inhibitors. See e.g., claims 64-66. Thus, Farand teaches the molecular therapeutic subject matter, therapeutically effective amount, pharmaceutical composition, pharmaceutically acceptable carrier/excipient, and additional HIV therapeutic-agent limitations encompassed by claims 1-3 and 51-53.
Farand teaches Compound 44 having the same molecular constitution and conventional stereochemistry as presently claimed Compound 1 and expressly reports Compound 44 as an atropoisomeric mixture. The instant specification similarly states at paragraph [077] that Compound 1 possesses two restricted rotational axes resulting in four atropisomers. Neither claim 1 nor claims 2-4 recite a particular atropisomer, atropisomeric configuration, atropisomeric purity, or ratio. Accordingly, Farand’s disclosure of Compound 44 as an atropisomeric mixture satisfies the molecular Compound 1 limitation under the broadest reasonable interpretation of claim 1.
Farand does not the presently claimed compound 44 in the particular crystalline form required by the claim, nor does Farand expressly disclose the claimed solid-state characterization thereof, including the XRPD characteristics recited in claim 4.
Shi teaches solid-form and polymorph screening of structurally closely related HIV therapeutic compound and demonstrate preparation of multiple crystalline forms thereof. See e.g., discussion of solid-state characterization and Examples directed to Compound 1 salts/cocrystals, see particularly the sodium salt crystalline Forms I-III, Figs. 1-6, and Tables 2-4. Shi teaches that different crystalline forms are identified by solid-state characterization techniques including XRPD and that DSC further assist in identifying and characterizing the crystalline form. Shi further teaches solvent-mediated polymorph screening in which solvates are generated using various solvents and subsequently dried/desolvated, In particular Shi teaches an acetonitrile (MeCN) solvate is converted upon drying/desolvation to crystalline Form I, including desolvation at about 50oC under vacuum, with the resulting crystalline material characterized by XRPD and DSC. See Example 3, Table 1. Shi further characterizes the resulting crystalline Forms I-III by XRPD and DSC, see Fig. 1-6 and Tables 2-4, also Examples 6-7 and Table 5. Shi demonstrates that crystalline forms provide desired or suitable properties, including stability, solubility, dissolution, manufacturability, purity, and processability. See column 6.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to subject the HIV therapeutic compound 44 taught by Farand to the solid form/polymorph screening procedures taught by Shi in order to obtain and characterize crystalline forms thereof. One of ordinary skill in the art would have been motivated to do so because Shi teaches that investigation and selection of crystalline forms of structurally related pharmaceutical compounds is useful for identifying solid forms having pharmaceutical desirable properties, including stability, solubility, dissolution, manufacturability, purity, and processability.
One of ordinary skill in the art would have had a reasonable expectation of successfully obtaining crystalline form because Shi does merely suggest that polymorph screening could theoretically be attempted but experimentally demonstrates preparation of multiple crystalline forms of a closely structurally related HIV therapeutic compound having conventional solvent-mediated solid-form screening. In particular, Shi teaches acetonitrile-containing crystallization/solvate conditions and conversion of solvated material to crystalline material upon drying/desolvation. Thus, the prior art provides both a reason to undertake the proposed solid-firm investigation and a reasonable expectation that application of the disclosed techniques to Farand’s pharmaceutical compound 44 would successfully produce crystalline material suitable for solid-state characterization.
With respect to claim 4, Shi further teaches crystalline forms obtained through solid-form screening are conventionally characterized by XRPD. The particular XRPD characteristics recited in claim 4 represent physical characteristics used to characterize the resulting crystalline material. As discussed above, with respect to the rejection under 35 U.S.C. 112(b), the specification does not establish that the limited XRPD characteristics recited in claim 4 uniquely define a crystalline Form distinct from the crystalline material reasonably resulting from the prior art solid form screening, particularly where claim 4 requires only three selected peaks.
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.
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Claims 1-4 and 51-53 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-40 of U.S. Patent No. 11,787,825B2 in view of Shi et al. (US11267799B2).
The patent claims disclose compounds useful for the treatment of HIV infection, including compound structurally corresponding to or closely related to Compound 1 presently claimed, and methods for their preparation, including 2-(2-(4-(A-(4-chloro-7-(2-((15)-l-(2-((3b5,4a/?)-5,5-difluoro-3- (trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrrol-l- yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l- yl)pyridin-3-yl)-l-(2,2,2-trifluoroethyl)-lH-indazol-3-yl)methylsulfonamido)-2-methyl-4- oxobutan-2-yl)-5-methyl-3-(phosphonooxy)phenyl)acetic acid (44). See claims. Patent claims further teach pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound together with one or more pharmaceutically acceptable carriers or excipients and teaches administration of such compositions of treatment of HIV infection. Farrand additionally teaches combination therapy in which the disclosed compounds are administered with one or more additional therapeutic agents, including HIV protease inhibitors. See e.g., claim. Thus, Patent claims teach the molecular therapeutic subject matter, therapeutically effective amount, pharmaceutical composition, pharmaceutically acceptable carrier/excipient, and additional HIV therapeutic-agent limitations encompassed by claims.
Patent claims teach Compound 44 having the same molecular constitution and conventional stereochemistry as presently claimed Compound 1 and expressly reports Compound 44 as an atropoisomeric mixture. The instant specification similarly states at paragraph [077] that Compound 1 possesses two restricted rotational axes resulting in four atropisomers. Neither claim 1 nor claims 2-4 recite a particular atropisomer, atropisomeric configuration, atropisomeric purity, or ratio. Accordingly, Patent claims’ disclosure of Compound 44 as an atropisomeric mixture satisfies the molecular Compound 1 limitation under the broadest reasonable interpretation of claim 1.
Patent claims do not the presently claimed compound 44 in the particular crystalline form required by the claim, nor do Patent claims expressly disclose the claimed solid-state characterization thereof, including the XRPD characteristics recited in claim 4.
Shi teaches solid-form and polymorph screening of structurally closely related HIV therapeutic compound and demonstrate preparation of multiple crystalline forms thereof. See e.g., discussion of solid-state characterization and Examples directed to Compound 1 salts/cocrystals, see particularly the sodium salt crystalline Forms I-III, Figs. 1-6, and Tables 2-4. Shi teaches that different crystalline forms are identified by solid-state characterization techniques including XRPD and that DSC further assist in identifying and characterizing the crystalline form. Shi further teaches solvent-mediated polymorph screening in which solvates are generated using various solvents and subsequently dried/desolvated, In particular Shi teaches an acetonitrile (MeCN) solvate is converted upon drying/desolvation to crystalline Form I, including desolvation at about 50oC under vacuum, with the resulting crystalline material characterized by XRPD and DSC. See Example 3, Table 1. Shi further characterizes the resulting crystalline Forms I-III by XRPD and DSC, see Fig. 1-6 and Tables 2-4, also Examples 6-7 and Table 5. Shi demonstrates that crystalline forms provide desired or suitable properties, including stability, solubility, dissolution, manufacturability, purity, and processability. See column 6.
It would have been obvious to one of ordinary skill in the art at the time the invention was filed to subject the HIV therapeutic compound 44 taught by Patent claims to the solid form/polymorph screening procedures taught by Shi in order to obtain and characterize crystalline forms thereof. One of ordinary skill in the art would have been motivated to do so because Shi teaches that investigation and selection of crystalline forms of structurally related pharmaceutical compounds is useful for identifying solid forms having pharmaceutical desirable properties, including stability, solubility, dissolution, manufacturability, purity, and processability.
One of ordinary skill in the art would have had a reasonable expectation of successfully obtaining crystalline form because Shi does merely suggest that polymorph screening could theoretically be attempted but experimentally demonstrates preparation of multiple crystalline forms of a closely structurally related HIV therapeutic compound having conventional solvent-mediated solid-form screening. In particular, Shi teaches acetonitrile-containing crystallization/solvate conditions and conversion of solvated material to crystalline material upon drying/desolvation. Thus, the prior art provides both a reason to undertake the proposed solid-firm investigation and a reasonable expectation that application of the disclosed techniques to Farand’s pharmaceutical compound 44 would successfully produce crystalline material suitable for solid-state characterization.
With respect to claim 4, Shi further teaches crystalline forms obtained through solid-form screening are conventionally characterized by XRPD. The particular XRPD characteristics recited in claim 4 represent physical characteristics used to characterize the resulting crystalline material. As discussed above, with respect to the rejection under 35 U.S.C. 112(b), the specification does not establish that the limited XRPD characteristics recited in claim 4 uniquely define a crystalline Form distinct from the crystalline material reasonably resulting from the prior art solid form screening, particularly where claim 4 requires only three selected peaks.
Conclusion
Claims 1-7 and 51-53 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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