Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This Office Action is responsive to the Response to Election/Restriction and Amendment filed 06/24/2026, wherein claim 60 is amended.
Claims 54-76 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant’s election without traverse of Group III, in the reply filed on 06/24/2026, is acknowledged.
Claims 54-59 and 61 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 60 and 62-76 are examined on the merits herein.
Claim Interpretation
In claims 60 and 62-76, form LT5 and LT3, are interpreted as a crystalline structure of lotilaner having the XRPD as depicted in instant Figures 7 and 4, respectively.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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.
Claim 64 is 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.
Claim 62 recites “Process for preparing a crystalline lotilaner designated form LT5.” However, claim 64, which depends from claim 62, recites “wherein the Lotilaner is form LT3.” Since LT5 and LT3 have distinct XRPD’s, it is not clear how lotilaner can have both form LT5 and LT3.
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 60 and 62-76 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2022/016490 to Chen (effectively filed 07/24/2020, IDS of 06/24/2026) in view of US 2003/0124028 to Carlson (published 2003, PTO-892) and Gardner (Computers and Chemical Engineering 28 (2004) 943-953, PTO-892).
Chen teaches a process for improving the enantiomeric purity of lotilaner comprising crystallization from a solvent selected from an alkyl alcohol, an alkyl cyanide, and an alkyl ketone, and compositions thereof (pgs. 13-14, claims 7-9).
Chen teaches purity of 98%, 99% and 99.9% or greater of crystalline lotilaner (pgs. 13-14, claims 4-6, 9).
Chen exemplifies a method of making a crystallized polymorph of lotilaner by adding thionyl chloride and stirring for 2-4 hours, to a reaction mixture of lotilaner in dimethyl carbonate heated to 40°C. The reaction mixture was stirred at 0-5°C for 2-4 hours. The reaction mixture was heated to 55°C and n-heptane was added at 55°C. Product seeds were added and the reaction was stirred at 55°C for one hour. N-Heptane was added dropwise and stirred at 55°C for three hours. The batch was gradually cooled to 35°C over three hours, and then to 20°C over three hours. The batch was filtered and the cake was washed with n-heptane. The compound was obtained after drying at 50°C under vacuum for 12 hours (pg. 10).
Regarding independent claim 60, since Chen teaches a method of treatment comprising administration of the composition to a patient, the composition necessarily has a pharmaceutically acceptable excipient (pg. 12, clause 17).
Chen differs from that of the instant claims in that it does not teach the XRPD of crystalline lotilaner form LT5 and the specific methods of making LT5.
Carlson teaches well-known systems for automated high-throughput preparation and screening of salts and polymorphs of drug candidates (emphasis added):
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(abstract). Carlson’s system specifically screens for polymorphs using a variety of techniques and solvents including heptane, isopropanol, and isoamyl alcohol (claim 1, [0019], [0143]-[0144], [0154]-[0177], Fig. 29), heating/cooling, acids ([0014]-[0019]; [0257]), seeding ([0131], [0141]), and isolating (claims 26-27).
Carlson specifically teaches:
-“a computer controls a process that is implemented to perform the pre-formulation process in accordance with the principles of the present invention. Several processes can be implemented in pre-formulation system. . .For example. . .Other processes may be implemented to generate, characterize and analyze different crystalline structures (e.g., polymorphs) of a compound. Comprehensive processes may involve a process that starts with a library design of solvents and ends with identification of a suitable active pharmaceutical ingredient” ([0099]);
-“Processing selected drug candidates or salts for discovery and characterization required at least two, but preferably at least three steps that are performs in a combinatorial or high throughput mode. One required step is dissolution of drug candidates or salts to form a solution. Another required step is crystallization (e.g., by evaporation, cooling or precipitation with an anti-solvent) of drug candidates or salts from the solution. An optional processing step prior to crystallization may include separating any remaining solids from the solution by filtration or centrifugation. This separation or filtering step may be performed to eliminate nucleation sites in the solvent provided to the crystallization step. Process 200 includes the preparation, crystallization, filtration, and other steps that are performed for salt selection” ([0119]);
-“Process 300 recrystallizes one or more drug candidates or salts (i.e., subjecting them to different conditions to generate as many polymorphs as possible, preferably substantially every polymorph, for a particular drug candidate or salt thereof) and screens each of the polymorphs in a high-throughput capacity. This enables process 300 to quickly characterize and determine those recrystallization conditions that are best for developing a desired drug ingredient that possesses a suitable crystalline structure. As used herein, recrystallization and crystallization conditions refer to those conditions that affect recrystallization. These conditions include, e.g., temperature, seeding (if present), solvent(s), etc.” ([0141]);
-“The number of solvents that may be used for polymorph generation and characterization may be any number desired. In one embodiment, the number of solvents is two, four, six, eight, 12, 16, 24, 36, 48, 96 or more. . .The term solvent in this respect means both a single solvent. .. as well as combinations of solvents” ([0144]);
-“Various recrystallization conditions (e.g., temperature, pressure, time, etc.) may be varied to provide various crystal formation” ([0147]);
-“The crystals may be screened for any physical property that would help characterize and/or identify a polymorph. The crystals may be screened for birefringence, melting point, solubility, hygroscopicity, IR pattern, Near IR pattern or Raman pattern, crystal morphology, X-ray powder diffraction pattern or any other suitable screening method to determine if crystals (or polymorphs) have formed” [0151]);
-“As illustrated in FIGS. 2A, 2B, and 3, processes use computer generated libraries as a template for preparing library members. For example, libraries containing various combinations of drug candidates, salts, crystals, and other re-formulation materials may be generated prior to library preparation. . .The materials in each library element 410 can differ by drug candidates, different known crystal structures of drug candidates, solvents, and salt reactants” ([0155]-[0156]);
-“A large number of solvents are known that can be used in recrystallization, either for salt selection and/or for polymorph generation. Tables 3 (shown in FIGS. 29A, 29B and 29 C) lists a number of exemplary solvents along with some of their physical properties. . .This process ensures that a wide variety of different types of solvents will be used for recrystallization which is advantageous for identifying polymorphs” ([0157]-[0165]; [0172]-[0174])
-“In another embodiment of a polymorph array, the array contains the drug candidate of interest mixed with compositions of two or more solvents, wherein each well contains a different solvent composition. . .In one embodiment the solvent compositions in the array or part thereof may be different concentrations of the two solvents relative to each other. The concentration of the solvents relative to one another may be any concentration desired. . .In another embodiment, solvent group design may be performed by providing a database containing information associating the physical or chemical properties of particular solvents with the production of crystallographic forms of drug candidates, identifying in the database which physical properties are associated with producing a large number of crystallographic forms, and designing new libraries using these identified physical or chemical properties as criteria for grouping solvents” [0176]-[0176]).
-Isopropanol (i.e., 2-propanol), heptane, and isoamyl alcohol (i.e., 3-methyl-1-butanol) as such solvents (Fig. 29A; [0372], Table 6);
-“Temperature is an important parameter in the various formulations, filtration, and crystallization operations that enable salt selection and polymorph production. For example in some methodologies it is desirable to heat reaction assembly 1500 to dissolve as much drug candidate as possible in the solvent(s). In processes where temperature is important (e.g., during crystallization), any of assemblies. . .may be placed in an oven, cooler, or other temperature-controlled chamber. . .It may be desirable in some processes to have precise control of temperature. One metho for controlling the temperature of the assemblies during certain stages of the workflow is shown in FIG. 23 ([0300]-[0304]).
Carlson’s system is similar to commercially available systems such as CRYSTALMAX as discussed by Gardner (pg. 947-949 “6.,” Figs. 4 and 5 describing CRSYALMAX).
Gardner specifically teaches:
-“Since isolation of a particular form from a crystallization process can be influenced by many processing variables and by the presence of other components such as impurities and degradants, it is important for the scale-up engineer to be able to understand the sensitivity of the process to these factors” (pg. 947, “4.”);
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(pg. 948);
-“In order to facilitate high throughput experimentation in form and formulation, we have developed a sophisticated informatics technology suite comprising four components: a design of experiment application, station controllers, an analytical application, and a set of process, analytical, and chemical databases. The design of experiment (DOE) application provides scientists with several tools for creating efficient combinatorial experiments. Although it is possible to run large, high throughput screens, it is very important to ensure that as many tested conditions as possible are viable and informative. Thermally driven crystallization, for example, can only occur if a material is soluble in a solution at a high temperature and supersaturated at a low temperature. . .The DOE application also has a module that allows for the creation of diverse primary experiments. . .This property space is then diversely populated with experimental conditions so that the space is evenly covered” (pgs. 951-952, “6.3.”).
Given the high level of skill in the art as evidenced by Chen, Carlson and Gardner, one of ordinary skill in the art would have considered the process application of Carlson’s technique using a commercially available system (such as Gardner’s) on Chen’s compound as “routine optimization” because it was well-known, commercially available, and a routine part of drug discovery (Gardner pg. 944-45, Figs. 2-3).
One of ordinary skill in the art would have had a reasonable expectation of success in producing Chen’s lotilaner solid forms Chen because Carlson and Gardner teach successful application to pharmaceuticals using these well-known techniques (Carlson, [0091], [0110], [0124]-[0126]) including variation of particular solvents and conditions (Carlson [0163]-[0165], [0261], Fig. 29), varying temperatures (Carlson [0026], [0138]-[0150], claims 43, 55-56), and seeding (Carlson [0141]). These conditions correspond to the same processes as instantly claimed.
As in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007) (“When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options with his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”), one of ordinary skill in the art would have known about the need to produce and select the optimal forms of the lotilaner identified by Chen, including the specific polymorphic forms which were known to be predictably discoverable by application of Carlson’s technique and was also within one of ordinary skill in the art’s technical grasp as evidenced by the commercially available system taught by Gardener. Thus, it would have been obvious to try and one of ordinary skill in the art would have anticipated success in the production endeavor since Gardener teaches that screening up to 18,000 crystallization conditions in parallel, having the capacity to conduct thousands of studies on one API, is known and well-established in the art.
At the time of the invention, there was an art recognized need to produce and identify the optimal solid form of a pharmaceutical as established by Carlson and Gardner (Carlson [0004]-[0005], [0010]-[0011]; Gardner Fig. 2, Fig 5, pgs. 944-946, “3.1,” 3.2,” “3.3”). The commercially available automated system that identifies “substantially every polymorph” evidenced by Carlson and Gardner provided a predictable solution to the problem of producing pharmaceutical solid forms. One of ordinary skill in the art would have pursued the procedures of the commercially available systems with a reasonable expectation of success because the systems were known to modify, by automated means, combinations and ratios of solvents, temperatures, and other reaction conditions, to identify “substantially every polymorph” (Carlson abstract) and Gardner demonstrated success with such commercial systems (Gardner pgs. 947-950, “6.,” “6.1.1,” “6.1.3,” Figs. 4 and 5 describing CRYSTALMAX). Similarly, one of ordinary skill in the art would have applied the known technique of pharmaceutical solid form optimization (Carlson; Gardner) to the lotilaner of Chen that would have yielded the predictable procedures to result in the optimal pharmaceutical solid form. Alternatively, one of ordinary skill in the art would have used the known technique that successfully identified the optimal solid form other pharmaceutical demonstrated by Gardner (sulfathiazole pg. 950 “6.1.3,” Fig. 10; Ritonavir pg. 949 “6.1.1”) and applied the known optimization technique in the same way to the lotilaner of Chen, where the result would have been predictable due to the explicit teaching of Carlson that the techniques were known to identify “substantially every polymorph.”
With each of the claims, the level of skill in the art is very high such that one of ordinary skill in the art would have considered routine the combination of elements from the teaching of the art in the same filed of endeavor. One of ordinary skill in the art would have recognized that the results of the combination would be predictable due to the well-known nature and optimizations routinely performed in the art. Thus, one of ordinary skill in the art would have arrived at the invention as claimed with a reasonable expectation of success.
Specifically regarding claims 62-62, isopropanol and n-heptane are taught as well known solvents for use in crystallization and methods of making polymorphs, and "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II).
Regarding the temperature ranges and times of heating, stirring and drying; "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation," MPEP 2144.05(II).
Therefore the claims are rejected as prima facie obvious.
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAUREN WELLS/Primary Examiner, Art Unit 1622
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