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 .
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 08/12/2025 has been entered.
Status of the Claims
Claims 1-20 are pending. Acknowledgment is made of the amendment of claims 1, 15, and 20 in the reply filed 08/12/2025.
Modified Rejections
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.
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.
Claims 1-6, 10, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Itsuji et al. (US 20140179795 A1).
Regarding the instant claims 1-6, 10, and 15-18, Itsuji et al. teaches, in paragraph [0084], a single embodiment where an aqueous pharmaceutical solution contains 1 w/v% acetaminophen, 0.56 w/v% glycine as a stabilizing agent, 0.22 w/v% of citric acid, and where the pH of the solution is 6.0. The instant specification defined “about” to be ±20%. Therefore, 0.22 w/v% citric acid is within “about 0.2 wt%”, as in instant claim 6.
Itsuji et al. teaches, in paragraph [0036], that the present invention is for stabilizing acetaminophen in order to prevent discoloration, caused by oxidation and hydrolysis, prevent precipitation, and prevent production of acetaminophen-related substances.
It is taught, in paragraph [0091], that “glycine effectively prevents degradation, oxidation and other modifications of acetaminophen in an aqueous composition, discoloration of the aqueous composition and precipitation in the aqueous composition”. Therefore, as in instant claims 1 and 15, glycine gives the solution chemical stability and prevents the degradation and oxidation of acetaminophen.
Itsuji et al. fails to specify that the chemical stability is exhibited for “at least 12 months”.
However, as evidenced by Allen (That drug expiration date may be more myth than fact, NPR, 18 July 2017) the Food and Drug Administration and pharmaceutical companies guarantee effectiveness for two or three years. It would be routine optimization to ensure that the solution exhibits chemical stability for at least 12 months, as in instant claims 1 and 15. MPEP 2144.05 II states: “‘[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 experimentation.’ In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.)”.
The purpose of the invention by Itsuji et al. is to create an acetaminophen solution that prevents discoloration, caused by oxidation and hydrolysis, prevents precipitation, and prevents production of acetaminophen-related substances. Therefore, it would be prima facie obvious to optimize or test the solution in order to determine if it is stable for at least 12 months. One would have a reasonable expectation in doing this since it is taught by Itsuji et al. that “glycine effectively prevents degradation, oxidation and other modifications of acetaminophen in an aqueous composition, discoloration of the aqueous composition and precipitation in the aqueous composition”.
Applicant Argues:
Applicant argues that “Itsuji et al. explicitly focuses on physical stability” and fails to disclose “chemical stability”. Applicant states that citric acid does not stabilize acetaminophen chemically in the composition, and Itsuji et al. fails to disclose degradation, hydrolysis, or oxidation.
Examiner Responds:
As included in the above rejection, Itsuji et al. teaches, in paragraph [0036], that the present invention is for stabilizing acetaminophen in order to prevent discoloration, caused by oxidation and hydrolysis, prevent precipitation, and prevent production of acetaminophen-related substances. It is taught, in paragraph [0091], that “glycine effectively prevents degradation, oxidation and other modifications of acetaminophen in an aqueous composition, discoloration of the aqueous composition and precipitation in the aqueous composition” (emphasis added). Therefore, all elements that Applicant stated are not taught in the prior art are indeed present. Additionally, stabilization of acetaminophen by citric acid is not a requirement of the claims.
Claims 7-9, 11-14, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Itsuji et al. (US 20140179795 A1), as applied to claims 1-6, 10, and 15-18 above, further in view of Oxycodone Hydrochloride and Acetaminophen Oral Solution (NDC 10702-238-50 from KVK-Tech, Inc., 12/05/2019).
Itsuji et al. teaches a solution containing 1 w/v% acetaminophen, 0.56 w/v% glycine as a stabilizing agent, 0.22 w/v% of citric acid, and where the pH of the solution is 6.0 (paragraph [0084]). Itsuji et al. also teaches that the acetaminophen concentration in the aqueous solution can be 0.1 to 5.0 w/v% (paragraph [0057]). It is taught that glycine gives the solution chemical stability and prevents the degradation and oxidation of acetaminophen. See above rejection.
Itsuji et al. fails to teach a specific embodiment where acetaminophen is 200-400mg/5mL and where oxycodone is 0.01-0.8 wt%.
The drug Oxycodone Hydrochloride and Acetaminophen Oral Solution, available from KVK-Tech, Inc. since 12/05/2019, is an aqueous acetaminophen solution containing the additional pharmaceutical oxycodone (an opioid analgesic/pain killer). This product contains 4.4815mg/5mL oxycodone (0.09 wt%), 325 mg/5mL acetaminophen, the weak organic acid edetate disodium, and the stabilizer PEG 400.
Regarding claims 7-9, 11-14, 19, and 20, it would be obvious to one skilled in the art to use the specific pharmaceutical dosages of acetaminophen and oxycodone present in the drug available by KVK-Tech, Inc. with the components of the stabilized aqueous acetaminophen solution taught by Itsuji et al. One would be motivated to do so because the dosages of acetaminophen and oxycodone are indicated for the management of severe pain (KVK-Tech, Inc., Indications and Usage). These dosages are used in order to treat patients whose pain treatment has not been tolerated or is not expected to be tolerated by acetaminophen alone, or to provide adequate analgesia to those not expected to receive adequate analgesia from acetaminophen alone (KVK-Tech, Inc., Indications and Usage).
One would have a reasonable expectation of success in using 4.4815mg/5mL oxycodone (0.09 wt%) and 325 mg/5mL acetaminophen in the composition taught by Itsuji et al., since neither of these changes would be expected to alter the shelf-life or cause oxidation products, since it is taught by Itsuji et al. that the glycine in the composition prevents degradation and oxidation.
Applicant Argues:
Applicant states that the prior art compositions cannot be combined because glycine cannot stabilize acetaminophen. Applicant states that Itsuji fails to disclose the chemical stability of acetaminophen.
Examiner Responds:
As discussed above, Itsuji et al. teaches, in paragraph [0091], that “glycine effectively prevents degradation, oxidation and other modifications of acetaminophen in an aqueous composition, discoloration of the aqueous composition and precipitation in the aqueous composition” (emphasis added). Therefore, the composition contains chemical stability due to the glycine, and combining the amounts of acetaminophen and oxycodone in the composition taught by Itsuji et al. in order to obtain a composition for severe pain management would not affect the stabilization of the composition.
New Rejections
Necessitated by Claim Amendment
Claim Rejections - 35 USC § 102
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 1-5, 7-10, and 15-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jordanova et al. (BG 107987 A, English translation included).
Jordanova et al. teaches, in claim 1 and Example 1, a liquid solution of 3.3% acetaminophen, 0.3% citric acid, and 15% ethylene glycol that has a pH of 5.0±0.5, as in instant claims 1-5, 10, and 15-18. The composition contains 3300 mg of acetaminophen per 100 mL, which is 165mg/5mL, as in instant claims 7 and 8. The specification defines “about” as ±20%. Therefore, 165mg/5mL is “about 200mg/5mL”, as in instant claim 9.
The solution is taught, in the abstract and Example IV, to be stable for three years, as in instant claims 1 and 15. The composition did not contain byproducts such as p-aminophenol after 36 months, as shown in the Stability Study Table.
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.
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.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Jordanova et al. (BG 107987 A, English translation included) as applied to claims 1-5, 7-10, and 15-18 above.
Jordanova et al. teaches, in claim 1 and Example 1, a liquid solution of 3.3% acetaminophen, 0.3% citric acid, and 15% ethylene glycol that has a pH of 5.0±0.5 See above rejection.
Jordanova et al. fails to teach a composition where the citric acid is about 0.1-0.2%, as in instant claim 6.
The instant specification defines “about” as ±20%. Therefore, about 0.1-0.2% citric acid includes 0.08-2.4% citric acid. The 0.3% citric acid taught in the composition by Jordanova is relatively close to 0.24%. MPEP 2144.05 I states: “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997)”.
Therefore, since the ranges are merely close to the prior art, the composition is rendered prima facie obvious in view of the composition taught by Jordanova et al.
Claims 11-14, 19, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Jordanova et al. (BG 107987 A, English translation included) as applied to claims 1-10, and 15-18 above, further in view of the drug Oxycodone Hydrochloride and Acetaminophen Oral Solution (NDC 10702-238-50 from KVK-Tech, Inc., 12/05/2019).
Jordanova et al. teaches, in claim 1 and Example 1, a liquid solution of 3.3% acetaminophen, 0.3% citric acid, and 15% ethylene glycol that has a pH of 5.0±0.5 See above rejection.
Jordanova et al. fails to teach the addition of oxycodone in the acetaminophen solution.
The drug Oxycodone Hydrochloride and Acetaminophen Oral Solution, available from KVK-Tech, Inc. since 12/05/2019, is an aqueous acetaminophen solution containing the additional pharmaceutical oxycodone (an opioid analgesic/pain killer). This product contains 4.4815mg/5mL oxycodone (0.09 wt%), 325 mg/5mL acetaminophen, the weak organic acid edetate disodium, and the stabilizer PEG 400.
Therefore, it would prima facie obvious to combine oxycodone with the composition taught by Jordanova et al. One would do this because the dosages of acetaminophen and oxycodone is indicated for the management of severe pain (KVK-Tech, Inc., Indications and Usage). These dosages are used in order to treat patients whose pain treatment has not been tolerated or is not expected to be tolerated by acetaminophen alone, or to provide adequate analgesia to those not expected to receive adequate analgesia from acetaminophen alone (KVK-Tech, Inc., Indications and Usage).
One would have a reasonable expectation of success in combining 4.4815 mg/5mL oxycodone in the composition taught by Jordanova et al. since the dosage form and other active ingredient is the same, and it also contains the same stabilizer. Since the composition taught by Jordanova et al. was taught to be free of oxidation products, such as p-aminophenol, for at least three years, the addition of oxycodone would not be expected to reduce the shelf life of this solution.
Conclusion
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RILLA M SAMSELL whose telephone number is (703)756-5841. The examiner can normally be reached Monday-Friday, 9-5.
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/R.M.S./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624