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 . This application claims priority to Sept 19, 2018.
Status of the Claims
Claims 1-2, 4-8, 10-20 and 23 are pending in this application and are directed to elected group I (pharmaceutical composition) and the species as follows.
• sebacoyl dinalbuphine (SDE) and acetaminophen (AAP);
• Eudragit S100 being the excipient species, as well as other excipients, such as sodium starch glycolate; and
• tablet being the form species. Support for such the elected species of tablet is provided in paragraphs 19-24, 33 and 35-36 of the specification, as well many other portions of the specification.
Response to Arguments
Applicant’s arguments, filed June 6 2025 with respect to the objection of claims 4 and 12 have been fully considered and are persuasive. The objection of claims 4 and 12 has been withdrawn.
Applicant’s amendments, filed June 6 2025 with respect to the rejection of claims 2, 6 and 17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ) have been fully considered and are persuasive. The rejection of claims 2, 6 and 17 has been withdrawn.
Applicant’s amendments, filed June 6 2025 with respect to the rejection of claims 4 and 12 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, have been fully considered and are persuasive. The rejection of claims 4 and 12 has been withdrawn.
Applicant’s amendment and arguments, filed June 6 2025 with respect to claims 5-8, 10-13, 15-20 and 23 being rejected under 35 U.S.C. 103 as unpatentable over US 20140221415 A1 Mouradian (US Pub ‘415) in view of US Patent 4237140 (US Pat ‘140) have been fully considered but they are not persuasive. See below rejection and response to Attorney arguments that follow.
New Claim Rejections Necessitated by Amendment - 35 USC § 112
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 5-8, 10-12, 15-20 and 23 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 5, 15 and 23 have been amended to recite the indefinite limitation to define the synergistic analgesic pharmaceutical preparation of combined sebacoyl dinalbuphine (SDE) to acetaminophen (AAP) ratio of 1:0.5 to 1: 20 “but excluding dosage combination of: (1) sebacoyl dinalbuphine 37.5 mg/kg and acetaminophen 200 mg/kg, (2) sebacoyl dinalbuphine 37.5 mg/kg and acetaminophen 300 mg/kg. . . . “
Dependent claims 6-8, 10-12, and 16-20 are similarly rejected.
The limitation to recite administered dosages of drug defined by mg/kg render the claim indefinite because they attempt to limit a composition per se (the synergistic analgesic comprising a first analgesic composition and a second analgesic composition), where the claimed dosages are by their nature, can only define a dosage administered to an intended subject in pain as they are defined in terms of mg weight of drug as per kg weight of the subject patient in need. In essence, the exclusionary negative limitation is an intended use to exclude these particular doses to a subject, rather than a limitation to define the physical properties of the claimed composition.
The negative limitation to exclude doses based on intended hypothetical patients based the patients’ weight cannot define the metes and bounds of a composition so as to place the public on notice as to when the claimed invention is being infringed upon or not. Note while claim 23 recites a method of treating pain in an intended subject in need, it is noted that the indefinite negative limitation is directed to the composition per se, where the first and second analgesic are in combination in the claimed weight ratio, but the indefinite limitation that attempts to exclude an intended subject in need cannot be applied to limited the claimed composition per se.
With regard to the method of claim 23, an amendment to incorporate the negative limitation to exclude the mg/kg of SDE and AAP to be directed to some type of method of administration step to the subject in need, rather than attempting to limit the claimed composition per se likely overcomes this indefinite rejection.
Maintained Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 5-8, 10-13, 15-20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2014/0221415 A1 Mouradian (US Pub ‘415) in view of U.S. Patent 4,237,140 (US Pat ‘140). Both references were previously cited.
Claim 5 is directed to a synergistic analgesic pharmaceutical preparation, comprising;
a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine (SDE), and
a second analgesic composition comprising a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP);
wherein the first analgesic agent and the second analgesic agent are combined in a weight ratio of sebacoyl dinalbuphine (SDE) to acetaminophen (AAP) of 1 :0.5 to 1 :20: but excluding dosage combination of: ( 1) sebacoyl dinalbuphine 37.5 mg/kg and acetaminophen 200 mg/kg, (2) sebacoyl dinalbuphine 3 7 .5 mg/kg and acetaminophen 300 mg/kg; and
wherein the synergistic analgesic pharmaceutical preparation has a longer analgesic duration and a higher AUC (Area Under Curve) value of analgesic effect and time compared to a sum of SDE alone and AAP alone.
See also claim 15, which is more or less directed to the same synergistic analgesic pharmaceutical preparations comprising (SDE) and (AAP) (in therapeutically effective amounts), with the same exclusion limitation.
See also new claim 23, a method of administering an analgesic pharmaceutical preparation, comprising: administering a therapeutically effective amount of a first analgesic agent (SDE) and a therapeutically effective amount of a second analgesic agent (AAP), together with one or more pharmaceutically acceptable excipients, with the same exclusion limitation.
While the claimed invention’s preambles of claims 5 and 15, recite a synergistic analgesic pharmaceutical preparation, it is noted that this intended use does not necessarily limit relevant prior art to methods of treating pain, i.e., analgesic combinations. Relevant art will include prior art teaching the claimed active ingredients sebacoyl dinalbuphine, aka SDE (a known prodrug of nalbuphine) and acetaminophen.
With regard the limitation of “wherein the synergistic analgesic pharmaceutical preparation has a longer analgesic duration and a higher AUC (Area Under Curve) value of analgesic effect and time compared to a sum of sebacoyl dinalbuphine alone and acetaminophen alone,” this limitation describes the function of the claimed combination preparation of sebacoyl dinalbuphine and acetaminophen. It does not add any patentable weight to the claimed preparation as the synergistic property of a combination of the two compounds compared to a sum of each analgesic alone would be naturally present in such a combination, whether expressly taught or not.
While claims 5 and 15 are noted to be amended in the preamble to recite the term “synergistic”, this limitation does not add patentable weight as it functionally describes the claimed pharmaceutical preparation comprising (i) a first analgesic composition comprising a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine (SDE), and (ii) a second analgesic composition comprising a therapeutically effective amount of a second analgesic agent which is acetaminophen( AAP); in the claimed weight ratios. As noted above, such synergistic property would be naturally occurring in the claimed combination.
Relevant to claims 5 and 15, Mouradian US Pub ‘415 teaches that while nalbuphine is an effective opioid analgesic (see paragraph 34), various formulations and prodrugs of nalbuphine (such as sebacoyl dinalbuphine) can prolong the retention of nalbuphine in the body to maintain a longer analgesic period. See para. 38.
Mouradian US Pub ‘415 teaches sebacoyl dinalbuphine not only has a prolonged retention compared to nalbuphine, it also has improved bioavailability, see paragraph 39. Mouradian teaches various pharmaceutical preparations its opioid analgesics, such as tablets, capsules, caplets, syrups, gels, etc., See paragraph 38
While Mouradian teaches the claimed prodrug of nalbuphine (SDE) for use in pharmaceutical compositions/preparations, it does not necessarily teach the use of this nalbuphine prodrug in combination with AAP in a pharmaceutical preparation.
However, one of ordinary skill in the art would arrive at the claimed invention with a reasonable expectation of success because nalbuphine combinations with acetaminophen are known in the art, where it is has been already established, that sebacoyl dinalbuphine is a prodrug of the base drug, nalbuphine, with improved pharmacokinetic properties (see Mouradian above).
Regarding claims 5 and 15, US Pat ‘140 teaches a synergistic combination of nalbuphine and acetaminophen (AAP) in a weight ratio of nalbuphine:AAP, of about 1:2 to about 1:70, with a carrier(s). See claim 1. See also Examples 1-3 recited in columns 3-4 of the ‘140 patent. Example 3 is reproduced below.
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Note, while the cited prior art does not teach the exclusion limitation of claims 5, 15 and 23, the art does encompass and overlap the first and second analgesic weight ratios as detailed above, so accordingly weight ratios claimed by Applicant and not excluded, are taught as detailed by US Patent ‘140 above.
US Patent ‘140 teaches its nalbuphine and AAP combination composition gives unexpectedly enhanced analgesic activity (synergy), i.e., the resulting activity is greater than the activity expected from the sum of the activities of the individual components. See column 2, lines 25-29.
Accordingly, the rationale to support a finding of obviousness are the known prior art elements (sebacoyl dinalbuphine is a known prodrug of nalbuphine, with improved analgesic properties, formulated in tablets and other pharmaceutical formulations, as per Mouradian US Pub ‘415) according to known methods (use of synergistic combinations of nalbuphine with acetaminophen as per US Pat ‘140) to predictably arrive at the claimed invention.
As required by the obviousness analysis, consideration of the fourth Graham factor requires considering objective evidence present in the application indicating obviousness or nonobviousness. Evidence is provided from the specification as follows.
Example 1 shows that the rats were orally dosed the claimed combination, sebacoyl dinalbuphine (SDE) 75 mg/kg plus acetaminophen (AAP) product (100 mg/kg), vs. SDE 75 mg/kg alone, AAP product (100 mg/kg) alone. See paragraph 51. While the specification exemplifies said combination dosage in rats, it does not provide a working example of the elected species of sebacoyl dinalbuphine (SDE), AAP and the excipient Eudragit S100 in a tablet form. However, support for such an elected species of tablet is provided in paragraphs 19-24, 33 and 35-36 of the specification, as well many other portions of the specification.
Additionally, the specification at paragraph 6 notes that that "the combination of nalbuphine and acetaminophen was not significant for any analgesic measurements, indicated the combination just have the additive effect of the components, as described in Jain, A. K. et al., "Comparison of Oral Nalbuphine, Acetaminophen, and Their Combination in Postoperative Pain," Clin. Pharmacol. Ther., 39(3):295-9 (1986).
However, such evidence regarding a lack of significance of any analgesic measurements of a combination of AAP and nalbuphine is tempered by the teachings of US Pat ‘140 that explicitly teaches and suggests a synergistic relationship between the two in treating pain.
Further, despite the statements from the Jain article (noted previously) and the Attorney arguments addressed below, regarding nalbuphine and acetaminophen, one of ordinary skill in the art would have a rationale to look towards combining sebacoyl dinalbuphine (the prodrug of nalbuphine) with AAP as Mouradian teaches the improved analgesic properties of the nalbuphine prodrug, sebacoyl dinalbuphine, versus nalbuphine, and because US Pat ‘140 teaches combinations of nalbuphine and acetaminophen exhibit a synergistic effect.
Accordingly, there is a lack of objective evidence to support a finding of nonobviousness over the cited prior art.
Regarding claims 6 and 17 that recite various excipients for the claimed formulation, US Patent ‘140 teaches modified starch, where the claimed excipient, sodium starch glycolate reads upon said prior art excipient of modified sodium starch. See Examples 1-3, columns 3-4.
Regarding claim 12 and the free form base of SDE, as noted above, Mouradian US Pub ‘415 teaches free form base of SDE. See paragraph 39.
Similarly, regarding claim 7 requiring one or more additional excipients as a carrier, US Patent ‘140 teaches various further excipients (modified starch, povidone, microcrystalline cellulose, etc.) as carriers for the claimed formulation. See Examples 1-3, columns 3-4.
Regarding claim 8 and the dose limitation wherein the amount of first and second analgesic is 1-1000 mg, US Patent ‘140 teaches Examples 1-3, where amounts of nalbuphine and AAP fall within the claimed/indefinite range, e.g., 325 mg AAP and 40 mg nalbuphine, see columns 3 and 4. Further as noted above, Mouradian US Pub ‘415 provides the rationale for the simple substitution of nalbuphine for SDE. See para. 39.
Regarding the limitations of claims 10-11 and 18-19 (synergism of combination vs. monotherapy of SDE and AAP alone; improved retention and bioavailability, etc.), such properties would be latent properties in a combination of the two, whether recited or not. Further, US Patent ‘140 teaches the synergism of the nalbuphine and acetaminophen combination (see column 2, lines 25-29). Further, Mouradian US Pub ‘415 teaches sebacoyl dinalbuphine has prolonged retention compared to nalbuphine in the body to maintain a longer analgesic period, as well as improved bioavailability. See paragraph 39.
Regarding claims 13, 16 and 20 and the elected species limitation of a tablet or in the form for oral administration, US Pat ‘140 teaches tablet formulations. See Examples 1-3, columns 3-4.
With regard to the method of treating pain of claim 23 comprising administering to the subject administering to the subject an analgesic pharmaceutical preparation comprising: a therapeutically effective amount of a first analgesic agent which is sebacoyl dinalbuphine (SDE)
and a therapeutically effective amount of a second analgesic agent which is
acetaminophen (AAP), together with one or more pharmaceutically acceptable excipients, it is noted that the teachings of Mouradian US Pub 415 in view of US Pat 140 combined render this method obvious as detailed with obviousness rejections of claims 5 and 15. See above. Therefore, the invention as a whole was prima facie obvious at the time it was invented.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response argues that the cited references, combined or individually do not disclose every limitation in independent claims 5, 15 and 23, an analgesic pharmaceutical preparation, comprising a therapeutically effective amount a first analgesic agent which is sebacoyl dinalbuphine and a therapeutically effective amount of a second analgesic agent which is acetaminophen (AAP).
In response, the above rejection renders the invention obvious as detailed above, addressing the limitations of SDE and AAP in therapeutically effective amounts.
The Attorney response argues the prolonged duration of analgesic effect is NOT due to SDE itself, as supported by the Hu Declaration (Sept 2025) Figure A and Table B, the AUC and Cmax values of plasma drug concentrating between SDE and NAL that do not show significant difference, which indicates that SDE does not exhibit the effects of an improved bioavailability and prolonged retention time compared to NAL.
In response, any evidence of unexpected results to overcome the prima facie case established must be commensurate in scope with the claimed invention, MPEP 716.02(d).
Here the data from Table A to demonstrate synergistic effects (The anti-nociceptive response compared to onset of action, duration of action and AUC value in rats after SDE), is specifically limited to doses administered to rat subject of oral SDE 75 mg/kg and AAP 100 mg/kg). As the rejected claims are far broader in scope (ratio range of 1:0.5 to 1:20) than a SDE 75 mg to AAP 100 mg ratio of 3: 4, the argument that Applicant has overcome the prima facie case fails, as the synergistic effects are limited to a single data point, a 3:4 ratio.
An amendment to the claims to recite ratio limitations approximate to the 3:4 ratio supporting the synergistic evidence of Table A would be allowable, i.e. as per MPEP 716.02(d), where the claims are considered to be commensurate in scope to the alleged synergistic and unexpected results. Applicants are reminded that it is the burden of Applicant to demonstrate unexpected results. MPEP 716.02(b).
The Attorney response argues that U.S. Pub ‘415 didn’t indicate that SDE has a longer retention time compared to NAL, as supported by the evidence of the Hu Declaration. Consequently, the prolonged analgesic duration of SDE+AAP is due to the synergistic effect, and the synergistic effect is unexpected.
In response, as detailed above, Table A data with regard to synergistic effects (prolonged duration time of action), is limited to particular data point, 3:4 ratio of SDE to AAP, (75 mg :100 mg). Accordingly, the argument that the synergistic effects overcome the prima facie case is insufficient as the scope of the claimed invention is far broader than the data point of 3:4 ratio said to be evidence of synergistic effects.
The Attorney response argues there are unpredictable synergistic effects in the combination of SDE and AAP, referencing Table A, where a combination of SDE and AAP according to the present invention exhibits unpredictable, superior longer duration of action and higher AUC value as compared with a combination of NAL and AAP. The response argues it would NOT be a simple substitution of NAL for SDE to provide a particular combination of SDE and AAP that achieves unexpected synergic analgesic effects according to the present invention.
In response, as detailed above, Table A data with regard to synergistic effects (prolonged duration time of action), is limited to particular data point, 3:4 ratio of SDE to AAP, (75 mg :100 mg). Accordingly, the argument that the synergistic effects overcome the prima facie case is insufficient as the scope of the claimed invention is far broader than the data point of 3:4 ratio said to be evidence of synergistic effects.
The Attorney response argues claims 5, 15, and 23 limit the weight ratio of SDE and AAP from 1:0.5 to 1:20, but exclude the dosage combination of SDE 37.5 mg/kg+ AAP 200 mg/kg and SDE 37.5 mg/kg+ AAP 300 mg, and the cited references do not disclose every recited limitation in the claims.
In response, as detailed above, the limitations regarding exclusion of doses of SDE 37.5 mg/kg+ AAP 200 mg/kg and SDE 37.5 mg/kg+ AAP 300 mg/kg, are indefinite, as they can only limit method of treatment and not a composition per se. In essence, they recite an intended use to exclude the claimed doses of mg/kg, which would properly a method administering the claimed composition, cannot limit the claimed composition per se.
Allowable Subject Matter
Claims 1, 2, 4, 13 and 14 are allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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