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 .
Withdrawn Rejection
The rejection of claim 6 under 35 U.S.C. 112(b) is withdrawn in view of the claim amendment.
Maintained Rejection
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
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 1-20, are rejected under 35 U.S.C. 103 as being unpatentable over Hanna et al. (US 2012/0149692Al) in view of Bekker et al. J Anaesthesiol Clin Pharmacol. 2018 Oct-Dec;34(4):450-457, FDA (https://www.accessdata.fda.gov/drugsatfda_docs/label/
2012/020938s022lbl.pdf), Pollak et al. The Clinical Journal of Pain 34(10):p 918-926, October 2018., Pi et al. Asian J of Pharm Sc, vol. 14, no. 2, Mar. 2019, pp. 154–64.
Regarding claim 1, Hanna (page 1, [0002]-[0010]) a method of treating pain in both human and animals by administering an oral composition (tablet, as an example) comprising meloxicam. According to the specification (page 8, line 29-33) oral solid pharmaceutical composition can either be capsules, tablets, pills, powders, and granules. Hanna does not explicitly teach meloxicam cocrystal for acute pain. However, Hanna (page 1, [0002]-[0012]) teaches meloxicam is a non-steroidal, anti-inflammatory (NSAID) and can be used as an analgesic to relieve pain in both humans and animals via oral administration. Hanna (page 1) also teaches novel crystalline forms of meloxicam, including cocrystals, which improves the rate of dissolution, leading to a faster therapeutic effect, or a rapid pain relieve compared to pure meloxicam. Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to recognize that cocrystal offering enhanced solubility and quicker onset which would provide superior pain relief, especially acute pain where rapid analgesia is clinically advantageous. Therefore, it would have been obvious to a POSITA to use the disclosed meloxicam cocrystals in a method for treating acute pain in a human subject because of rapid dissolution and fast onset of action would lead to faster pain relieve.
Regarding claim 2, Hanna does not explicitly teach post-surgical pain.
However, Bekker (page 450, abstract, page 452-453) teaches the use of a daily dose of intravenous (IV) meloxicam nanocrystal to reduce post-surgical pain compared to placebo. Bekker (page 451) also teaches that pure oral meloxicam is rarely used for acute post-operative pain due to its poor dissolution and delayed onset of action. Thus, as applied to claim above, it would have been obvious to a POSITA to modify the teachings of Hanna in view of Bekker’s disclosure to utilize meloxicam cocrystal, having an improved therapeutic profile including enhanced dissolution and faster onset of action compared to meloxicam nanocrystal, to treat acute post-operative pain. This is supported by Pi (page 155) disclosing that the primary purpose of both cocrystals and nanocrystals formulation is to overcome challenges associated with poor aqueous solubility, low dissolution rate, and limited oral absorption of drugs, which directly impact bioavailability and plasma concentration. Therefore, a POSITA would be highly motivated to administer meloxicam cocrystal to achieve quicker analgesia and arrive at the claimed invention, because severe post-operative pain requires fast analgesia intervention which can be achieved via a superior bioavailability of the drug.
Regarding claim 3-4, Hanna does not explicitly teach meloxicam nanocrystal.
However, Hanna (page 5, [0116], [0157]) teaches microsized meloxicam by sieving powders to 53–75-micron size to control and reduce the effect of particle size dissolution rate, before being suspended and orally administered. As demonstrated by Bekker (page 450-451) disclosing the use of meloxicam nanocrystal to treat acute pain, particularly post-surgical pain; and that such formulation significantly improves drug dissolution and onset action. Additionally, Bekker (page 451-453) teaches phase 2 and 3 studies have been conducted assessing IV nanocrystal meloxicam for acute post-operative pain management, including patient pain measurements comparing meloxicam nanocrystal with placebo, showing significant pain reduction in the treated group with IV nanocrystal. Thus, the combined teachings of Hanna and Bekker clearly indicate that particle size significantly improves dissolution and onset action, which would motivate a POSITA to formulate meloxicam as either cocrystal or nanocrystal to arrive at the claimed invention. Thus, formulation of meloxicam as nanocrystals or cocrystals is a routine and predictable strategy to further enhance dissolution, oral absorption, therapeutic efficacy and the overall therapeutic properties of the drug.
Therefore, given Bekker teaches an IV formulation, it would have been obvious to a POSITA to substitute IV treatment to an oral formulation, because oral medication is generally considered less invasive than IV routes and is often preferred by patients, possibly leading to better treatment compliance. Furthermore, given (FDA, page 1) that meloxicam is commonly available in oral formulations, including tablets, thus switching from IV to oral formulation is a predictable variation, and the pharmacokinetic profile is an inherent property of the drug and dose.
Regarding claim 5, Bekker (page 452-453, table 1) teaches meloxicam is prescribed or administered orally at 7.5 mg, 15 mg and 22.5 mg dose; IV formulation is administered at 15 mg, 30 mg and 60 mg dose; whereas Hanna ([0004]) teaches meloxicam is prescribed as a tablet (7.5 and 15 mg dose) for human subjects. Given Hanna and Bekker already disclose meloxicam doses for both IV and oral formulations, it would have been obvious to a POSITA to combine the teachings of Hanna and Bekker to select a broader range of 1 to 50 mg meloxicam cocrystal that falls within the disclosed doses by the references with the expectation that such adjustment would lead to the desired efficacy and pharmacokinetic outcomes.
Regarding claim 6, Hanna does not explicitly teach reduced mean time or reduced median time of first perceptible relief, as an example.
However, Bekker (page 451 and 453), as applied to claim 3-4 above, teaches phase 2 and 3 studies have been conducted assessing IV nanocrystal meloxicam for acute postoperative pain management, showing significant pain reduction, highlighting its faster onset of analgesia compared to placebo. Hanna (page 1, [0009]- [0010]) teaches meloxicam cocrystal can enhance the rate of dissolution, shorten Cmax, resulting to a quicker onset of pain relief. Thus, it would have been obvious to a POSITA to understand that this faster onset of analgesia corresponds to a reduced median or mean time to the first perceptible compared to placebo. This supported by Pollack (page 923) teaches IV meloxicam nanocrystal significantly reduces the perceptible pain relief and the median time to meaningful pain relief compared to placebo in patients with moderate-to severe postoperative pain. Therefore, it would have been obvious to a POSITA to combine the teachings of Bekker, Hanna, FDA and Pollak to arrive at the claimed invention, because both meloxicam cocrystal and nanocrystal enhanced dissolution and faster onset of action, leading to a reduction in median time, as example.
Regarding claims 7-8, Hanna does not explicitly teach twice daily administration.
However, Bekker (page 450-451, abstract; page 453; page 456) teaches the use of a single dose of IV meloxicam nanocrystal for management of acute post-operative pain, due to fast onset of analgesia and long duration of effect compared to placebo group. However, medication titration and adjustment of dosing frequency are standard practices to optimize therapeutic efficacy and to manage side effects. For example, the FDA-approved label for meloxicam specifies flexible dosing, for instance, starting at 7.5mg once daily and titrating up to 15 mg once daily (which is equivalent to taking two 7.5mg tablet once or twice daily). This demonstrates that dose and frequency selection are routine steps guided by patient need and clinical judgment. Therefore, it would have been obvious with reasonable expectation of success to a POSITA at the time of filing of the instant application to look at the combined guidance from Bekker, Hanna and FDA to make the dosing once or twice daily and arrive at the claimed invention.
Regarding claim 9, the combined teachings of Hanna and Bekker do not explicitly teach a person diagnosed with an opioid use disorder (OUD).
However, Bekker (page 450-453) teaches IV meloxicam nanocrystal reduces opioid use in post-operative patients. Thus, it would have been obvious to a POSITA to recognize that minimizing opioid use is a key therapeutic goal in treating patients with OUD. Therefore, it would have been obvious to a POSITA to combine the teachings of Bekker, Hanna and FDA to administer oral meloxicam nanocrystal or cocrystal to reduce acute pain in patients diagnosed with OUD, since these patients would benefit from opioid-sparing pain management. Consequently, extending meloxicam’s use to this population would be a routine and predictable application of the Bekker’s teachings because patients with OUD frequently experience pain.
Regarding claims, 10-11, Hanna (page 9-10, [0172] and [0184]) teaches the meloxicam cocrystal can be selected from meloxicam:succinic acid cocrystal (2:1) and meloxicam: salicylic acid cocrystal form I (1:1), as an example.
Regarding claims 12-14, as applied to claims 5, 7-8 above, Hanna (page 1-2) teaches one of the limitations of pure meloxicam is the low aqueous solubility and that the mean peak plasma concentration, Cmax, for meloxicam is achieved within four to five hours. For this reason, Hanna (page 1-2) teaches that novel meloxicam cocrystal formulation overcomes this limitation, leading to an improved rate of dissolution, shortening Cmax or peak plasma concentration, and a quicker onset of pain relief. As example, Hanna (page 6, Table 3 and Table 4) discloses cocrystal meloxicam therapeutic plasma concentration can include, but not limited to, 300 ng/ml, 870 ng/ml and 1282.5 ng/ml within 5 min, 30 min and 60 min, respectively. In addition, Pollak (page 925) teaches IV meloxicam nanocrystal displays a rapid onset of analgesia, which was evident as early as 15 to 30 min after administration. As mentioned above in the 103 rejection, Pi (page 155) dicloses that the primary purpose of both cocrystals and nanocrystals formulation is to overcome challenges associated with poor aqueous solubility, low dissolution rate, and limited oral absorption of drugs, which directly impact bioavailability and plasma concentration. Therefore, it would have been obvious to a POSITA to combine the teaching of Hanna, FDA, Bekker and Pi to formulate an oral meloxicam cocrystal or nanocrystal to achieve a therapeutic blood plasma concentration of meloxicam of less 0.5 hours or at a concentration between 500-2500 ng/ml, because of poor bioavailability of pure meloxicam, leading to a delayed Cmax.
Regarding claim 15-20, as applied to claims 5, 7-8, 12-15 above, Hanna (page 1 and 5) teaches pure meloxicam is prescribed as tablet (7.5 and 15 mg dose). Hanna (page 5) teaches a dose of 1mg/kg administered to a 250-300 g rat corresponds to a human equivalent dose of approximately 9.72-11.34 mg for a 60 kg adult (based on standard dose conversion between
animals and human). As evidence by Nair (page 27-31) discloses formula for dose conversion between animals and human (Nair et al. J Basic Clin Pharm. 2016 Mar;7(2):27-31).
This range aligns closely with the claimed meloxicam-equivalent doses of about 10 mg or 15 mg. Given that oral meloxicam is routinely prescribed at 7.5 mg and 15 mg once daily, and that the rat dosing falls within the expected pharmacologically active range when scaled to humans, thus a POSITA would have found it obvious to correlate the rat dose with the claimed human-equivalent dose. As applied to claims 12-15 above, and as also demonstrated by Hanna (page 6, Table 3 and Table 4) disclose cocrystal meloxicam therapeutic plasma concentration can include, but not limited to, 300 ng/ml, 870 ng/ml and 1282.5 ng/ml within 5 min, 30 min and 60 min, respectively.
Although, Hanna’s pharmacokinetic data were collected in rats, the combined teachings of Hanna, FDA, Pi and Bekker confirm that meloxicam is prescribed for both humans and animals. It is also well established in pharmaceutical practice that rat or other animal pharmacokinetic models are routinely used to predict human pharmacokinetics, particularly for oral drug administration, because rats are a standard preclinical model widely accepted for their predictive relevance. As evidence by Robarge (abstract; page 13-15) discloses that rats pharmacokinetic data can be used to predict human pharmacokinetic, especially clearance and bioavailability. Robarge et al. (Antibodies (Basel). 2024 Dec 24;14(1):2.)
Therefore, it would have been obvious with a reasonable expectation of success that a POSITA would be highly motivated to achieve the recited pharmacokinetic profiles in humans simply by applying the combined teachings of Hanna, Pollak, Pi, Bekker and FDA’s teachings regarding pain management with oral meloxicam cocrystal or nanocrystal using similar dosing, formulation, and concentration. Thus, using the same drug, at similar doses for the same indication, inherently would produce plasma concentrations within the claimed ranges, as evidenced by Hanna’s teachings about meloxicam cocrystal blood plasma concentration can include, but not limited to, 300 ng/ml, 870 ng/ml and 1282.5 ng/ml within 5 min, 30 min and 60 min, respectively. Therefore, it would have been obvious to a POSITA to combine the teaching of Hanna, FDA, Bekker and Pi to formulate an oral meloxicam cocrystal or nanocrystal to achieve a therapeutic blood plasma concentration of meloxicam of less 0.5 hours which correspond to a concentration between 500-2500 ng/ml, as an example.
Furthermore, it would have been obvious to a POSITA to modify Hanna’s teachings with the disclosure of Bekker and FDA on the use of meloxicam cocrystal or nanocrystal to treat acute post-surgical pain with pharmacokinetic parameters inherent to the meloxicam cocrystal or nanocrystal formulation to arrive at the claim invention. Therefore, the combined references describe the same compound inherently expects these claims including the pharmacokinetic parameters, associated properties relating to meloxicam cocrystal blood plasma concentration. See MPEP 2112.01.
Response to Argument
Applicant argues that Hanna does not teach meloxicam cocrystals formulated as a solid oral dosage form e.g., table, and does not teach use of such formulations for the treatment of acute pain. Applicant’s argument is not persuasive because at the time of the invention, meloxicam was already known, approved and marketed as a solid oral dosage form specifically tablets. Furthermore, given that meloxicam cocrystal improved meloxicam stability or bioavailability, a POSITA would expect meloxicam cocrystals to be incorporated into the same type of oral dosage forms already used for meloxicam in clinical practice. Regarding acute pain, meloxicam’s analgesic and anti-inflammatory properties are well-established in the art. Therefore, a POSITA would recognize that any oral meloxicam formulation would inherently be applicable to known therapeutic uses of meloxicam, including acute pain. For this reason, a POSITA would also recognize that intended use limitation do not confer patentable distinction where the underlying pharmaceutical composition and dosage form are already known in the art.
Applicant argues that Bekker does not cure the deficiencies of Hanna, thus the combined teachings of Hanna and Bekker are not obvious. Applicant’s argument is not persuasive because Bekker explicitly teaches the use of meloxicam in post-operative pain management, which is a well-recognized form of acute pain. By highlighting the clinical importance and effectiveness of meloxicam in this acute setting, Bekker would motivate a POSITA to seek improved formulations of meloxicam to enhance therapeutic performance. Therefore, contrary to Applicant’s assertion, the combined teachings of Bekker and Hanna clearly disclose improved meloxicam cocrystals and a POSITA would logically be motivated to formulate such improved solid forms to known acute pain indication, including but not limited to post-surgical pain.
Applicant further argues that Pi does not cure the deficiencies of Hanna and Bekker. Applicant also argues that Pi teaches away because the reported nanocrystals show a Tmax of 1.58 hrs, which corresponds a longer pain relief. Applicant’s argument is not persuasive because Pi clearly teaches cocrystal and nano-cocrystal strategies significantly improved dissolution rate, oral absorption, and bioavailability of poorly soluble drugs. These formulation principles are not limited to baicalein and would reasonably motivate a POSITA to apply similar approach to meloxicam, as described by Hanna, particularly for known acute pain indications established by Bekker. Therefore, contrary to Applicant’s assertation, the combined prior art reinforces the benefits of meloxicam cocrystals and provide clear motivation a POSITA would pursue to improve meloxicam’s oral performance. Furthermore, Applicant’s argument regarding Tmax is not persuasive because Applicant selectively relies on a single reported Tmax value while ignoring the full data set in Table 2. For instance, according to Table 2, multiple BE-NCT formulation exhibit Tmax values well below 1 hr, including 0.53±0.54 h; 0.37±0.40 h; and 0.28±0.19, demonstrating rapid absorption for nano-cocrystals formulation, resulting in short pain relief. Even the cited Tmax 1.58±0.98 h reflects substantial variability, with lower bound well below 1 hr, indicating faster absorption in within the reported range. This variable is common in pharmacokinetic studies and would not be interpreted by a POSITA as discouraging or teaching away, contrary to Applicant’s assertation. Overall, Table 2 as a whole demonstrate consistently higher Cmax and dramatically increased AUC values for nano-cocrystal formulation, confirming improved oral absorption and bioavailability; thus, this would motivate, rather than discourage a POSITA to apply such approach to improve meloxicam solubility, absorption and shorter pain relief.
In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 PQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Furthermore, it is important to highlight that the combined teachings of Hanna, Bekker, Pi and Pollack teach that cocrystals and nano-cocrystals significantly improve meloxicam oral absorption and dissolution which can be effective against acute pain. Therefore, the combined teachings of the prior art would reasonably motivate a POSITA to apply cocrystals or nanocrystals to meloxicam, and arrive at the claimed invention.
Regarding Robarge, Applicant’s argument is not persuasive, the reference is used to indicate evidence of common general knowledge in the art and it is not part of the rejection statement. Its primary function is show that a POSITA would have reasonably understood that rats pharmacokinetic data can be used to predict human pharmacokinetic and extrapolate the data to human, when evaluating oral formulations, as an example.
Claims 3 and 4
Applicant argues that Bekker does not teach meloxicam nanocrystals or intravenous (IV) meloxicam nanocrystals formulation and a POSITA would unlikely to convert an IV meloxicam formulation into an oral dosage form. Applicant’s argument is not persuasive because Bekker’s primary goal is to demonstrate that a nanocrystal meloxicam dispersion overcomes poor dissolution and slow onset, directly linking the technology to better acute pain management.
Given that Bekker also mentions multiple meloxicam routes (e.g., oral, rectal, transdermal and IV), thus, a POSITA would understand that using nanocrystal technology in tablet formulations would also improve dissolution and, in turn, enhance meloxicam’s performance in pain management. Furthermore, a POSITA would recognize that poor oral dissolution causes delayed pain treatment and yet that a nanocrystal formulation presents a better option and would be logically motivated to apply the same nanocrystal principle to oral dosage form, aiming for faster onset and better bioavailability.
Claim 9
Applicant argues that Bekker does not teach treating patients diagnosed with an opioid use disorder and does not teach that such patients would benefit from opioid-sparing pain management. Applicant’s argument is not persuasive because Bekker clearly teaches meloxicam as an effective non-opioid analgesic for post-operative pain and discusses its role in reducing reliance on opioid analgesics and opioid-related adverse effects. By presenting meloxicam, particularly IV nanocrystal meloxicam, as an effective option that reliably reduces opioid consumption in the perioperative setting; thus, contrary to Applicant’s view, Bekker directly teaches an opioid-sparing approach that a POSITA would logically apply to patient at high risk for opioid use disorder, where minimizing opioid exposure is essentially critical.
Conclusion
Therefore, claims 1-20 are rejected
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622