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 . 1
Continued Examination Under 37 CFR 1.114
A Request for Continued Examination under 37 CFR § 1.114, including the feeset forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since thisapplication is eligible for continued examination under 37 CFR § 1.114, and the fee setforth in 37 CFR § 1.17(e) has been timely paid, the finality of the previous Office actionhas been withdrawn pursuant to 37 CFR § 1.114. Applicant's submission filed on 19 March 2026 has been entered.
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.
Information Disclosure Statement
At this time, and information disclosure statement has not been filed.
Response to Arguments
Applicant’s amendments and accompanying statements, filed 19 March 2026 with respect to the rejection of claims 5-8, 10-12, 15-20, and 23 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 The rejection of claims 5-8, 10-12, 15-20, and 23 has been withdrawn.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. The previous rejection of the claims has been overcome as claims 5, 15 and 23 have been amended to recite a weight ratio between SDE and AAP, with negative limitations to exclude particular weight ratios. However, the claims are newly rejected under the same art (US Pub ‘415 and US Pat ‘140). See below rejection and response to Attorney arguments that follow.
Note, claim 2 was previously stated to be allowable. While the claim is patentable over the prior art, it is now objected to as detailed below.
Claim Objections
Claim(s) 2 and 6 are objected to because of the following informalities:
Claim 2, line 3 recites the typos “Polv” and “methac l ylate,” reproduced below, rather than “Poly” and “methacrylate.”
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Claim 2, line 7 recites the typo “polyvinvlpvrrolidone,” reproduced below, rather than “polyvinylpyrrolidone.”
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Claim 6, line 3 recites the typo “methacrvlate,” reproduced below, rather than “methacrylate.”
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Claim 6, line 7 recites the typo “polvvinylpyrrolidone,” reproduced below, rather than “polyvinylpyrrolidone.”
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Appropriate correction is required.
Claim Interpretation
While claims 5 and 15 preambles recite the term “synergistic analgesic”, this limitation does not add patentable weight as it functionally describes the claimed pharmaceutical preparation comprising sebacoyl dinalbuphine (SDE) and acetaminophen( AAP), in the claimed weight ratios. Such synergistic property would be present in prior art teaching the claimed combination, whether explicitly recited or not.
With regard to 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 (in terms of longer analgesic duration and higher AUC) 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 disclosed or not in the art.
Claims 5, 15 and 23 recite negative limitations to exclude SDE (the prodrug of nalbuphine) to acetaminophen (AAP) weight ratios of 3:16 and 1:8. These limitations are rejected for being new matter (see below). They are also addressed in the obviousness rejection below.
Claim Rejections - 35 USC § 112 (Lack of Written Description/New Matter)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-8, 10-13, 15-20 and 23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection per MPEP 2163.06.2 Note that claims 6-8, 10-13 and 16-20 are similarly rejected as being dependent upon their rejected independent claims 5, 15 and 23.
Claims 5, 15 and 23 have been amended to exclude specific weight ratios of sebacoyl dinalbuphine to acetaminophen, 3:16 and 1:8. This exclusion (i.e., negative) limitation is not supported by the specification as originally filed.
Rather, support for these exclusionary/negative limitations can only be found in Figure C and Table D (paragraphs 12-15) of the Hu Declaration, dated and signed on July 11, 2023 and submitted with Applicant’s response dated Sept 8 2023. The latest Attorney response dated March 19, 2026 confirms this at page 12, second to last full paragraph, where dosage ratios of 37.5 mg/kg to 200 mg/kg (weight ratio of 3:16 SDE to AAP) and 37.5 mg/kg and 300 mg/kg (weight ratio 1:8 SDE to AAP), were noted not have synergistic activity per Table D and Figure C. There is no basis to exclude these weight ratios in the specifically as originally filed.
In fact, the specification recites weight ratios which are specifically intended to include these excluded weight ratios. See paragraph 24, last line, reproduced below.
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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.
Currently amended claim 5 is directed to a synergistic analgesic pharmaceutical preparation, comprising:
(i) a first analgesic composition comprising a therapeutically effective amount of
a first analgesic agent which is sebacoyl dinalbuphine, and
(ii) a second analgesic composition comprising a therapeutically effective
amount of a second analgesic agent which is acetaminophen;
wherein the first analgesic agent and the second analgesic agent are combined in a weight ratio of sebacoyl dinalbuphine to acetaminophen of 1:0.5 to 1:20,
excluding the weight ratio of:
(1) sebacoyl dinalbuphine to acetaminophen of 3:16, and
(2) sebacoyl dinalbuphine to acetaminophen of 1 :8; 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 sebacoyl dinalbuphine alone and
acetaminophen 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), together with one or more pharmaceutically acceptable excipients with the same exclusion limitations.
See also claim 23, a method of treating pain in a subject in need comprising: administering to the subject sebacoyl dinalbuphine and acetaminophen (AAP) with weight ratio of sebacoyl dinalbuphine to acetaminophen of 1 :0.5 to 1:20, excluding the weight ratio 3:16 and 1:8.
As detailed above, the claim 5 and 15 preambles of synergistic analgesic properties of the claimed pharmaceutical preparations are merely functionally descriptive limitations that would be present in the cited prior art teaching the claimed combination.
Further, the functional descriptive 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,” is present in the cited prior art teaching the claimed pharmaceutical preparation.
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 SDE (a nalbuphine prodrug) in combination with AAP in a pharmaceutical preparation.
Nor does Mouradian US Pub ‘415 teach the claimed exclusion limitation of sebacoyl dinalbuphine to acetaminophen of 3:16 and sebacoyl dinalbuphine to acetaminophen of 1:8.
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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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.
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 claimed SDE to AAP weight ratios as detailed above, so weight ratios claimed by Applicant and not excluded, are taught as detailed by US Patent ‘140 above. See MPEP 2144.05, Prima Facie obviousness of similar and overlapping ranges.
While the cited art does not teach the exclusion of 3:16 and 1:8 of SDE to AAP ratios, it is noted that such limitations are new matter without support of the originally filed specification (see above 35 USC 112(a) rejection). Further, US Pat ‘140 teaches a range of weight ratios that overlap the claimed weight ratios.
The claimed weight ratio is 1:0.5 to 1:20 (SDE:AAP), where US Pat ‘140 teaches nalbuphine : AAP, of about 1:2 to about 1:70. See claim 1.
While the negative limitation excludes weight ratios of 3:16 and 1:8, it allows for claimed weight ratios adjacent, such as 4:16 (aka 1:4), 5:16 , 1:7, 1:9 to 1:10, where these claimed weight ratios are encompassed by the taught ratios of US Pat ‘140, about 1:2 to about 1:70.
Prior to the filing of the present application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of Mouradian US Pub ‘415 (sebacoyl dinalbuphine (SDE) is a known prodrug of nalbuphine, with improved analgesic properties, formulated in tablets, etc.) in combination with acetaminophen (AAP), based on the teachings synergistic combinations of nalbuphine with AAP of US Pat ‘140. See MPEP 2143(a), combining prior art elements according to a known method to obtain predictable results, i.e. the claimed combination of SDE and AAP.
The PHOSITA has a reasonable expectation of success because nalbuphine combinations with acetaminophen are known in the art (US Pat ‘140), where known SDE is a prodrug of the base drug, nalbuphine, with improved pharmacokinetic properties (see Mouradian above).
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.
Note that while the claims have been noted to exclude particular ratios (3:16 and 1:8), the claimed ratio nonetheless contain other weight ratios adjacent to those excluded (such as 4:16 and 1:7 to 1:9 or 1:10) where these claimed weight ratios are encompassed by the teachings of US Pat ‘140, about 1:2 to about 1:70.
Regarding claims 6 and 17, US Patent ‘140 teaches various claimed excipients including 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.
Similarly, regarding claim 7, US Patent ‘140 teaches one or more additional carrier 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 claim 12, Mouradian US Pub ‘415 teaches free form base of SDE. See paragraph 39.
Regarding claims 13, 16 and 20, US Pat ‘140 teaches the elected species of an orally administered 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 sebacoyl dinalbuphine and acetaminophen (AAP) with weight ratio of sebacoyl dinalbuphine to acetaminophen of I :0.5 to I :20, excluding the weight ratio
3:16 and 1:8, 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.
RESPONSE TO ATTORNEY ARGUMENTS:
The Attorney response states that there are unpredictable synergistic effects m the combination of SDE and AAP, as claimed and described, referencing Table 1 (page 12 of the specification), to show synergism of the combination versus cumulative data of SDE and AAP alone, such as longer duration of action, higher absorption (bioavailability) and higher AUC value.
The Attorney response states Dudzinski (US Pat ‘140) only shows a summation effect of NAL (not SDE) and AAP, not synergism, referencing data from the Hu Declaration of July 2023, later referencing Figure C and Table C of the Hu Declaration to provide support for the exclusion of ratios 3:16 and 1:8. The Attorney response argues it would not be a simple substitution of SDE for NAL due to the synergistic effect.
In response, the claims are obvious as detailed above, including the exclusion weight ratio limitations.
The Examiner has noted previously, 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. This was done with allowable claim 1 reciting such 3:4 ratio. 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).
Applicant references Table C to argue synergistic effects. An example of this is reproduced below, where at doses of SDE 37.5 mg/kg and AAP 65 mg/kg, equivalent to a weight ratio of 1: 17.33, a combination of the two demonstrated a greater effect with AUC and duration of action than each alone.
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It is noted that the alleged synergistic effects, while considerably greater than the sum cumulative effect of SDE and AAP alone, would be expected to occur as follows.
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.
Further, 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.
Allowable Subject Matter
Claims 1, 4, 13 and 14 are allowed. Note that objected claim 2 would be allowable but for the objection due to typographical errors.
Conclusion and 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.
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, 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
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
1 This application claims priority to Sept 19, 2018.
2 f new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). The examiner should still consider the subject matter added to the claim in making rejections based on prior art since the new matter rejection may be overcome by applicant.
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