DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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.
Claim Status
Claims 2-6, 8-27, 30-32, 34-52, 55-68, 71-94, 96-99, 101-105, 108-137, 140-153, 155-165, 168-183, and 186-189 are cancelled.
Claims 1, 7, 28-29, 33, 53-54, 69-70, 95, 100, 106-107, 138-139, 154-155, 166-167, and 184-185 are pending.
Claims 100, 106-107, 138-139, 154-155, 166-167, and 184-185 are withdrawn.
Claims 1, 7, 28-29, 33, 53-54, 69-70, and 95 are examined on the merits in this prosecution.
CLAIM REJECTIONS
Indefiniteness Rejection
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.
Claims 7, 53, and 70 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 pre-AIA the applicant regards as the invention.
Claim 7, second line, and claim 53, second and third lines, recite the term “such as.” The phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 70 is confusing as presented, and the Examiner cannot determine what elements or combination of elements is being claimed within the apparent multiple embodiments. Put another way, it is not possible for the Examiner to determine with a degree of certainty which claimed elements are in which embodiments.
Anticipation Rejection
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.
1) Claims 1, 7, and 53-54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pagire (“Microwave assisted synthesis of caffeine/maleic acid co crystals: the role of the dielectric and physicochemical properties of the solvent,” Cryst Eng Comm, 2013, 15, 3705–3710; cited on IDS dated 10/29/2024), as evidenced by the Facilities list of Universidad Complutense Madrid (downloaded 4/27/2026 from https://www.ucm.es/nazariomartingroup/facilities) and the National Library of Medicine monograph “Caffeine” (downloaded 4/28/2026 from https://web.archive.org/web/20190820171657/https://www.ncbi.nlm.nih.gov/books/NBK519490/, dated 8/20/2019) .
Pagire teaches microwave radiation has been used to prepare the 1 : 1 and 2 : 1 co-crystals of caffeine and maleic acid (Abstract). Pagire teaches microwaves enhance molecular mobility via excitation of molecular rotations through the interaction between the microwave radiation and the rotating dipoles of the molecule by the process of dielectric heating (pg 3705, right column).
The limitation of “the pharmaceutical composition comprises at least 50% of the API” is interpreted as a mole:mole ratio of API (caffeine) and this limitation is met by Pagire.
For claim 7, Pagire teaches microwave heating is provided by a Monowave 300 microwave reactor from Anton Paar. The evidentiary reference of the Facilities list of Universidad Complutense Madrid discloses the Monowave 300 microwave reactor operates at a microwave frequency of 2455 MHz, corresponding to 12.24 cm, in each case within the claimed range.
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caffeine maleic acid
For claims 53 and 54, caffeine is well known in the art as a central nervous system stimulant (psychoactive stimulant), useful for promoting wakefulness (see the evidentiary document “Caffeine” from NCBI).
Obviousness Rejections
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
1) Claims 28-29 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Pagire (cited above), in view of Kulkarni (“Stoichiometric Control of Co-Crystal Formation by Solvent Free Continuous Co-Crystallization (SFCC),” Cryst. Growth Des. 2015, 15, 5648−5651), as evidenced by the Facilities list of Universidad Complutense Madrid (cited above).
The teachings of Pagire are discussed above.
Pagire does not teach an extrusion method of processing a co-crystal between caffein and maleic acid.
Kulkarni teaches the missing element of Pagire.
Kulkarni teaches extrusion as a method of purification, specifically that stoichiometric control can be achieved by solvent free continuous co-crystallization by control of parameters such as extrusion temperature (Abstract).
For claim 33, Kulkarni teaches the following (pg 5649, left colum):
Caffeine showed two endothermic peaks at 156 and 236 °C. Maleic acid exhibited a single endothermic melting peak at 143 °C followed
by degradation at higher temperature indicated by an out of shape recovery of the endothermic peak. DSC thermograms from the physical mixture in 1: 1 ratio showed a first endothermic peak at 100 °C, significantly lower than the melting point of the either component which may be due to eutectic formation. This was followed by a further endothermic peak at 104 °C which may be attributed to the
melting of 1:1 co-crystal formed during DSC. The physical mixture in 2:1 ratio showed multiple endothermic peaks at 97, 100, and 104 °C, again lower than the melting point of either component. The peaks at 97 and 100 °C may be due to the eutectic formation in different ratios and the peak at 104 °C might be due to the melting of 1:1 co-crystal formed during heating past the eutectic temperature. These peaks were followed by uneven events similar to those with the 1: 1 ratio except that an additional peak was observed at 235 °C, which was attributed to melting of unutilized caffeine in the mixture.
Based on the results of thermal analyses, caf:ma acid cocrystallization experiments were conducted in a twin screw extruder (Pharmalab, ThermoScientific, UK with screw diameter 16 mm and length to diameter ratio 40:1) at set temperatures below and above the eutectic temperature at a screw speed of 10 rpm. The screws were configured to produce mixture 1:1, caf:ma co-crystals 1:1, caf:ma physical mixture 2:1, and caf:ma co-crystals 2:1. Caf:ma 1:1 co-crystals showed an endothermic peak at 104 °C, whereas caf:ma 2: 1 co-crystals exhibited an endothermic peak at 118 °C….
The skilled artisan would have expected success in carrying out the extrusion purification process on the mixture of 1:1 and 2:1 caffeine to maleic acid product of Pagris because Kulkarni teaches a mixture comprising 1:1 and 2:1 caffeine to maleic acid co-crystals can be purified utilizing a twin screw extruder at set temperatures below and above the eutectic temperature at a screw speed of 10 rpm.
2) Claims 69 and 70 are rejected under 35 U.S.C. 103 as being unpatentable over Pagire (cited above), in view of Leyssens (“Importance of Solvent Selection for Stoichiometrically Diverse Cocrystal Systems: Caffeine/Maleic Acid 1:1 and 2:1 Cocrystals,” Cryst. Growth Des. 2012, 12, 1520−1530), as evidenced by the Facilities list of Universidad Complutense Madrid (cited above).
The teachings of Pagire are discussed above.
Pagire does not teach the physical nature of the attractive forces in the co-crystal.
Leyssens teaches the missing element of Pagire.
Leyssens teaches “structural X-ray diffraction analyses of both the 2:1, as well as the 1:1 polymorphic phases [of the caffeine/maleic acid cocrystals], show an out of plane maleic acid compound. The carboxylic acid groups are oriented in such a manner to promote intermolecular formation of hydrogen bonded synthons.” See Abstract.
The person of ordinary skill in the art would have found it obvious that the non-covalent interaction between both the 2:1 and the 1:1 cocrystal of caffeine and maleic acid are the result of formation of hydrogen bonds between caffeine and maleic acid since the data obtained by Leyssens from single crystal x-ray diffreaction supports the structures as in Schemes 1 and 2 (pg 1521), shown below:
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3) Claim 95 is rejected under 35 U.S.C. 103 as being unpatentable over Pagire (cited above), in view of Zaworotko (US 2015/0250797) , as evidenced by the Facilities list of Universidad Complutense Madrid (cited above).
The teachings of Pagire are discussed above.
Pagire does not teach a formulation comprising an excipient or one or more formulation steps.
Zaworotko teaches the missing element of Pagire.
Zawortko teaches nutraceutical compositions comprising a co-crystal comprising a co-crystal former and a nutraceutical compound (Abstract). Zawortko teaches nutraceutical co-crystals may be readily incorporated into a pharmaceutical composition by conventional means, and may further comprise a pharmaceutically-acceptable diluent, excipient or carrier (pg 12, [0148]).
The skilled artisan would have expected success in adding an excipient to a co-crystal of caffeine-maleic acid of Pagire because Zawortko teaches pharmaceutical compositions such as tablets contain a pharmaceutically acceptable carrier or diluents as excipients. See also pg 9, [0119]).
CONCLUSION
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL P COHEN whose telephone number is (571)270-7402. The examiner can normally be reached on M-Th 8:30-5:30; F 9-4.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana S. Kaup, can be reached on (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL P COHEN/Primary Examiner, Art Unit 1612
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