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 .
Response to Amendment
2. Applicant's amendment and response, filed September 11, 2025, has been reviewed by the examiner and entered of record in the file.
3. Claims 35, 53 and 54 are amended, and claims 55 and 56 are cancelled.
4. Claims 35-37, 42, 43, and 49-54 are under examination and are the subject of this office action.
Information Disclosure Statement
5. The information disclosure statement (IDS) submitted on September 11, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the signed copy of Applicant’s PTO-1449 form, attached herewith.
Previous Claim Rejections - 35 USC § 103
6. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
7. Claims 35-37, 42, 43, and 49-53 remain rejected under 35 U.S.C. 103 as being unpatentable over Della Valle et al., (U.S. 20150328173 A1), as evidenced by Morgan and Christie, (British Journal of Pharmacology 2011), and further in view of CDC Guideline for Prescribing Opioids for Chronic Pain (Morbidity and Mortality Weekly Report, published March 18, 2016).
It is noted that the disclosure of prior-filed provisional Application No. 62/164,618 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application, regarding the recited ratio of oxycodone to PEA, as well as the dosage ranges of both oxycodone and PEA. Accordingly, the instant claims are entitled to benefit of priority to PCT/IL2016/050519, filed May 17, 2016.
Claim 35, as amended, is drawn to a method for preventing at least one side-effect caused by oxycodone consumption in a human subject in need thereof, wherein the at least one side-effect is caused by consuming a single dose of oxycodone and is selected from irritation, confusion, uncontrolled movement and/or disorientation (more specifically, irritation (claim 53)),
comprising administering to the subject the single dose of oxycodone or a salt thereof in a pharmaceutical composition further comprising palmitoyl-ethanolamine (PEA) or a salt thereof, in a molar ratio of the oxycodone to PEA between about 1:1 and about 1:100, thereby preventing the at least one side-effect,
wherein the pharmaceutical composition comprises a human equivalent dose of oxycodone of less than or equal to about 0.42 mg/kg,
and wherein administration of the oxycodone and the PEA is repeated (claim 52).
8. Della Valle et al. teach a method of treating pain conditions in a subject in need thereof comprising the administration of N-palmitoylethanolamine (PEA) in combination with an opioid, wherein PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance (paragraph [0042]). Della Valle et al. teach the combined, simultaneous administration of PEA and an opioid (see abstract and paragraphs [0017]-[0018]). In particular, Della Valle et al. disclose the combined administration of PEA and morphine in an animal model, (see paragraphs [0037]-[0041] and Figure 1).
9. Although Della Valle et al. do not specifically disclose an embodiment comprising the administration of a unit dose composition comprising PEA and oxycodone, as recognized by In re Schaumann, 572 F.2d 312 (CCPA 1978), claims to a species are anticipated where the prior art teaches a genus embracing a limited number of members closely related to each other such that one of ordinary skill in the art could immediately envisage each member. Notably, in In re Petering, 301 F.2d 676 (CCPA 1962) the court determined that a prior art genus containing only 20 compounds anticipated a claimed species within the genus because "one skilled in [the] art would... envisage each member" of the genus (emphasis in original)). Della Valle et al. specifically name oxycodone within the small genus of preferred opioids (paragraph [0024]). In consideration of the fact that the preferred genus comprises only nineteen opioids, the skilled artisan would have immediately envisaged substituting oxycodone for morphine in the Experiment embodied in paragraphs [0037]-[0042], in the preparation of a pharmaceutical composition for administration to delay opioid tolerance in a subject in need thereof.
10. And, the rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In the instant case, PEA and an opioid could be combined in a single composition for efficiency of administration, with the expected result of a composition suitable for the delay of opioid tolerance associated with opioid consumption.
11. Regarding the duration of opioid administration, CDC is aware of opioid tolerance and toxicity and recommends administering oxycodone for a total of three days or less:
“[s]everal guidelines on opioid prescribing for acute pain from emergency departments (192–194) and other settings (195, 196) have recommended prescribing ≤3 days of opioids in most cases,” [emphasis added]
(page 24, left column, last paragraph).
Less than three days embraces the limitation of “the single dose of oxycodone” required by claim 35. And, the optimization of result effect parameters (in this case, duration of administration) is obvious as being within the skill of the artisan.
12. Regarding the dosage amount of oxycodone, CDC discloses a dosage amount of 10 mg oxycodone per tablet dose (page 48, Table 2 summary), which is within the range of about 0.42 mg/kg or less, required by instant claim 35 (assuming an average human weight of 62 kg, 10 mg/62 kg = 0.161 mg/kg). CDC guides physicians to prescribe opioids at the lowest possible effective dose:
“[e]xperts agreed that when opioids are needed for acute pain, clinicians should prescribe opioids at the lowest effective dose and for no longer than the expected duration of pain severe enough to require opioids to minimize unintentional initiation of long-term opioid use,”
(Page 24, right column, first full paragraph).
13. And, the optimization of known effective amounts of known active agents to be administered is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that "[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 optimization with a reasonable expectation of success. Thus, one of skill in the art would be motivated to employ oxycodone in the lowest possible effective dose, for the shortest duration of administration, in order to minimize side effects and toxicity, and delay opioid tolerance.
14. As such, Della Valle et al. suggest the combined administration of PEA and oxycodone for the treatment of pain in a subject in need thereof, wherein said administration delays the side effect of opioid tolerance, but are silent as to the prevention of irritation in said subject.
15. Yet, as evidenced by Morgan, “all opioids that produce analgesia also can cause tolerance, addiction and withdrawal,” (page 1323, left column, first full paragraph) wherein acquired opioid tolerance is defined as the gradual reduction in the intrinsic sensitivity of opioid receptors (page 1328, right column, first full paragraph), which leads to not only markedly increased doses being required to achieve the desired effect, but in the absence, symptoms of withdrawal. Notably, withdrawal is characterized by irritability (page 1330, left column, section under “Dependence and withdrawal,” lines 8-12).
16. Therefore, by virtue of administering PEA to delay/ mitigate opioid tolerance in a subject in need thereof, one is preventing the side effect of withdrawal/ irritability caused by opioid consumption. One of skill in the art before the effective filing date of the claimed invention would have been motivated to administer PEA in combination with an opioid, because PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance, thereby preventing the side effect of withdrawal/ irritability caused by opioid consumption, with a reasonable expectation of success.
As such, claims 35, 49, 52-53 are prima facie obvious.
Claim 36 is drawn to claim 35, wherein the molar ratio between the oxycodone or a salt thereof, and the PEA or a salt thereof is between about 1:2 and about 1:80. Claim 37 is drawn to claim 35, wherein the molar ratio between the oxycodone or a salt thereof, and the PEA or a salt thereof is between about 1:2.5 and about 1:5.
17. Regarding the molar ratios recited in claims 35-37, the molar ratio of PEA to the opioid drug (oxycodone) is a result-effective variable. It would have been customary for one of skill in the art to determine the optimal molar ratio in order to best achieve the desired results. See also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005), "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.” Thus one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer PEA in combination with an opioid, because PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance, thereby preventing the side effect of withdrawal/ irritability caused by opioid consumption, and optimize the molar ratio of opioid drug (oxycodone) to PEA, with a reasonable expectation of success.
As such, claims 36 and 37 are prima facie obvious.
Claim 42 is drawn to claim 35, wherein the pharmaceutical composition comprises about 200-1800 mg of PEA or a salt thereof. Claim 43 is drawn to claim 42, wherein the pharmaceutical composition comprises about 250 mg, about 500 mg, about 750 mg, about 1000 mg or about 1500 mg of PEA or a salt thereof.
18. Della Valle et al. additionally teach that PEA is to be administered at a dose of between 3 and 50 mg/kg (paragraph [0028]), which is equivalent to a dosage range of 186 to 3100 mg (assuming an average adult human subject weight of 62 kg), which fully embraces the ranges required by claims 42 and 43. Thus one skilled in the art before the effective filing date of the claimed invention would have been motivated to administer PEA in combination with an opioid, because PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance, thereby preventing the side effect of withdrawal/ irritability caused by opioid consumption, and optimize the dosage range of PEA, with a reasonable expectation of success.
As such, claims 42, and 43 are prima facie obvious.
Claim 49 is drawn to claim 35, and limits wherein the pharmaceutical composition is formulated for systemic administration, more specifically oral, oral mucosal, nasal, sublingual, inhalational, topical, rectal, vaginal, parenteral, intravenous, intramuscular, or subcutaneous administration (claims 50 and 51).
19. Della Valle et al. teach oral administration, buccal (i.e., sublingual), as well as parenteral administration including rectal, intramuscular, implantation (i.e., topical), and subcutaneous (paragraphs [0029] and [0032]-[0035]). And, optimization of variables of a known process such as route of administration is routine to one skilled in the art. Thus one would readily consider selecting any of the above routes of administration named by Della Valle et al. to administer the composition of PEA and oxycodone to a subject in need thereof. One of skill in the art before the effective filing date of the claimed invention would have been motivated to administer PEA in combination with an opioid, because PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance, thereby preventing the side effect of withdrawal/ irritability caused by opioid consumption, and optimize the route of administration, with a reasonable expectation of success.
As such, claims 49-51 are prima facie obvious.
20. In the alternative, claims 35 and 54 remain rejected under 35 U.S.C. 103 as being unpatentable over Della Valle et al., U.S. 20150328173 A1, as evidenced by Morgan, (British Journal of Pharmacology 2011), as applied to claims 35-37, 42, 43, and 49-53 above, and further in view of Riley et al., (Journal of Pain and Symptom Management 2015).
Claim 35, as amended, is drawn to a method for preventing at least one side-effect caused by oxycodone consumption in a human subject in need thereof,
wherein the at least one side-effect is caused by consuming a single dose of oxycodone and is selected from irritation, confusion, uncontrolled movement and/or disorientation (more specifically, confusion, uncontrolled movement and/or disorientation (claim 54)).
comprising administering to the subject the single dose of oxycodone or a salt thereof in a pharmaceutical composition further comprising palmitoyl-ethanolamine (PEA) or a salt thereof, in a molar ratio of the oxycodone to PEA between about 1:1 and about 1:100, thereby preventing the at least one side-effect, wherein the pharmaceutical composition comprises a human equivalent dose of oxycodone of less than or equal to 0.42 mg/kg,
21. As detailed above, Della Valle et al. as evidenced by Morgan teach the administration of a composition comprising PEA and oxycodone for the treatment of pain in a subject in need thereof, wherein said administration prevents side effects of opioid tolerance including withdrawal/ irritation, but are silent to the side effects of confusion, uncontrolled movement and/or disorientation in said subject.
22. Yet, Riley et al. assess the side effects of opioid tolerance, specifically oxycodone, and resulting withdrawal, in particular confusion, disorientation, and myoclonus, i.e., uncontrolled movement, (Page 167, Table 3). As such, one skilled in the art would reasonably expect that by administering a combination composition to mitigate/prevent opioid tolerance in a subject in need thereof, one is necessarily mitigating the side effects of confusion, uncontrolled movement and/or disorientation. One of skill in the art before the effective filing date of the claimed invention would have been motivated to administer PEA in combination with an opioid, because PEA successfully mitigates the effects of opioid tolerance/ delays the development of opioid tolerance, thereby preventing the side effect of confusion, uncontrolled movement and/or disorientation caused by opioid consumption, with a reasonable expectation of success.
As such, claims 35 and 54 are prima facie obvious.
Response to Arguments
23. Applicant traverses the previous obviousness rejection over Della Valle in view of Morgan, and argues the following points:
(i) Applicant argues that the claimed invention pertains to the prevention of side effects caused by consuming a single dose of oxycodone, not a post hoc treatment to address withdrawal or other symptoms after commencing or termination oxycodone use. Applicant alleges that Della Valle teaches repeated dosing and a need to delay the development of morphine tolerance for treating persistent pain and does not teach preventing side effects caused by consuming a single dose of opioid. Applicant amended claim 35 to recite a human equivalent dose of less than or equal to 0.42 mg/kg. Applicant argues that one skilled in the art would not expect a lower human equivalent dose of oxycodone to achieve an analgesic effect and would therefore not consider administering it in combination with PEA. Applicant argues that CDC teaches repeated administration because physical dependence on opioids is an expected physiological response in patients exposed to opioids for more than a few days” (CDC, page 24, left column, first paragraph).
24. Applicant's arguments have been fully considered but they are not persuasive. Regarding the duration of opioid administration, CDC is aware of opioid tolerance and toxicity and recommends administering oxycodone for a total of three days or less:
“[s]everal guidelines on opioid prescribing for acute pain from emergency departments (192–194) and other settings (195, 196) have recommended prescribing ≤3 days of opioids in most cases,” [emphasis added]
(page 24, left column, last paragraph).
Less than three days embraces the limitation of “the single dose of oxycodone” required by claim 35. And, the optimization of result effect parameters (in this case, duration of administration) is obvious as being within the skill of the artisan.
25. Regarding the dosage amount of oxycodone, CDC discloses dosage amounts of 10 mg tablets (page 48, Table 2 summary), wherein a 10 mg tablet dose is within the range of 0.42 mg/kg or less, (assuming an average human weight of 62 kg, which is equivalent to about 0.161 mg/kg). CDC guides physicians to prescribe opioids at the lowest possible effective dose:
“[e]xperts agreed that when opioids are needed for acute pain, clinicians should prescribe opioids at the lowest effective dose and for no longer than the expected duration of pain severe enough to require opioids to minimize unintentional initiation of long-term opioid use,” (Page 24, right column, first full paragraph).
26. Thus, based on the guidance of CDC, nothing unobvious is seen in one of skill in the art combining PEA with oxycodone and reducing the number of oxycodone doses to a single dose, wherein the human equivalent dose is less than or equal to about 0.42 mg/kg.
27. It is noted that while Applicant argues that the low human equivalent dose of oxycodone unexpectedly achieves an analgesic effect in combination with PEA, the unexpected results demonstrated in the examples in the Specification are limited to a molar ratio of oxycodone to PEA of from 1:2.5 to 1.5 (Tables 1 and 2 at pages 26-27). According to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." As Applicant has not established that molar ratios beyond this range are effective, it is recommended that the claims be amended so that they are consistent with the results demonstrated in the Specification.
(ii) Applicant argues that Morgan is directed to preventing opioid withdrawal after stopping opioid treatment, contrary to the teachings of Della Valle and CDC, such that the references irreconcilably conflict. Applicant alleges that Della Valle teaches prolonging opioid treatment, while CDC teaches the importance of shortening opioid treatment. Applicant contends that Morgan and Della Valle are not combinable because Della Valle teaches combination therapy to delay tolerance while continuing to receive morphine; while Morgan teaches preventing withdrawal after stopping long term opioid treatment
Applicant argues that Riley does not resolve the alleged deficiencies of Della Valle in view of Morgan because Riley does not teach or suggest the combined administration of PEA and an opioid. Applicant alleges that Riley is directed to switching opioids to treat cancer-related pain if the first opioid is ineffective, rather than adding an additional agent such as PEA.
28. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, Della Valle motivates one skilled in the art to administer the combination of PEA and oxycodone to a human subject in need thereof. Morgan is relied upon for evidencing side effects of opioid consumption, in particular tolerance and withdrawal symptoms. Likewise, Riley is relied upon for demonstrating the intolerable side effects of oxycodone tolerance and resulting withdrawal, specifically, confusion, disorientation, and myoclonus/uncontrolled movement. The fact that Riley suggests switching opioids to mitigate resulting intolerable adverse reactions does not negate the fact that Riley specifically teaches that oxycodone consumption results in side effects of confusion, disorientation, and uncontrolled movement.
29. Thus, nothing unobvious is seen in administering the instantly recited combination of oxycodone and PEA in a single dose to a subject in need thereof, thereby preventing the necessary side effects of opioid consumption, including tolerance and/or withdrawal, and symptoms thereof.
30. It is noted that the unexpected results demonstrated in the examples in the Specification are limited to a molar ratio of oxycodone to PEA of from 1:2.5 to 1.5 (Tables 1 and 2 at pages 26-27). According to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." As Applicant has not established that molar ratios beyond this range are effective, it is recommended that the claims be amended so that they are consistent with the results demonstrated in the Specification.
Conclusion
31. In conclusion, claims 35-37, 42, 43 and 49-54 are pending in the application, and all claims are rejected.
32. 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.
33. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628