FINAL 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 .
Status of the Claims
This action is in response to papers filed 07/22/2026 in which claims 12 and 20 were canceled; claims 7-11, 13, 17-19, and 21 were withdrawn; claims 1-3, 5-6, 14, and 16 were amended; and claim 22 was newly added. All the amendments have been thoroughly reviewed and entered.
Claims 1-6, 14-16, and 22 are under examination.
Withdrawn Objections/Rejections
The Examiner has re-weighted all the evidence of record. Any rejection and/or objection not specifically addressed below is hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
New Rejections
Necessitated by Applicant’s Claim Amendments
Claim Rejections - 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 and 16 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.
Regarding claims 5 and 16, the recitation of “the iron species” renders said claims 5 and 16 indefinite because claims 5 and 16 are dependent from claims 1 and 2, respectively and thus, there is lack of antecedent basis for the iron species in claims 1 and 2. As such, it is not clear what “the iron species” are claims 5 and 16 referencing to, as the compositions of claims 1 and 2 do not contain an iron species.
As a result, claims 5 and 16 do not clearly set forth the metes and bounds of patent protection desired.
Claim Rejections - 35 USC § 103
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 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(s) 1 and 3-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over of Sokol et al (Acta Poloniae Pharmaceutica—Drug Research, 2011, 68(2): 169-177; previously cited) in view of Abe et al (Chem. Pharm. Bull., 8 August 2020, 68: 1008-1012), and as evidenced by Niedzielski et al (Environ Sci Pollut Res., 2018, 25: 242-248).
Regarding claims 1 and 3-6, Sokol teaches a pharmaceutical composition containing ranitidine HCl and trace amount of iron (Fe(II)) (Abstract; pages 169, right column to page 176, right column), thereby “trace amount” meets the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III).” It is noted that the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III)” encompassed a composition which can contain zero amount of iron (III), as “less than” would include no amount of the iron(III) and thus, trace amount of iron (Fe(II)) of Sokol stands to read on the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III).” Alternatively, the pharmaceutical composition of Sokol being produced using river water would contain a trace amount of both iron(II) and iron (III), as Sokol teaches the presence of metal ions that include but not limited to Fe(II) ions, and as evidenced by Niedzielski, river water naturally contains both iron(II) and iron (III) in their oxidized form (iron oxide) (Niedzielski: Abstract; pages 243-247).
While Sokol does not expressly teach the composition contains less than 160 ppb, less than 80 ppb, or less than 17 ppb of N-nitrosodimethylamine (NDMA) by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days,” as recited in claims 1, 3 and 6, respectively, it would have been obvious to provide the composition of Sokol such that the composition is storage stable and contains amount of NDMA that is less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days per guidance from Abe.
Abe teaches that nitrosodimethylamine (NDMA) is a known impurity in ranitidine products during the manufacturing process and in high-temperature storage (Abstract; Introduction; pages 1010-1012). Abe teaches the FDA accepted daily intake limit for NDMA in ranitidine drug substance is 0.32 ppm (less than 320 ppb) (Abstract; pages 1010-1011). Abe highlights the risk of NDBA formulation in ranitidine formulations when extrapolated to storage under ambient conditions, and a force-degradation study under the stress condition (60°C for 1 week) strongly suggested that environmental factors such as moisture and oxygen are involved in the formation of NDMA in ranitidine formulation (Abstract; pages 1010-1011). Abe further teaches that storage of ranitidine tablets and reagent powders at high temperatures also increased the amount of nitrite, which is considered one of the factors influencing NDMA formations, and these data indicate that the necessity of controlling/monitoring stability-related factors, in addition, to controlling impurities during the manufacturing process, in order to provide stable ranitidine product by mitigating the safety risk of these products throughout their lifecycle (Abstract; pages 1010-1012). Abe showed that the amount of NDMA during storage at 60°C/75% RH in a vacuum vial, in which the air has been removed and hermetically sealed with a lid to prevent moisture/oxygen infiltration, was about 0.2 ppm (about 200 ppb) at Day 7 (Abstract; pages 1010-1012; Figs 2-4).
It would have been obvious to one of ordinary skill in art to provide the composition of Sokol such that the composition is storage stable and contains amount of NDMA that is less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because an ordinary artisan knowing the drawbacks of NDMA impurities in ranitidine products during manufacturing process and storage per Abe would have looked to mitigating this NDMA impurities in the ranitidine composition Sokol by controlling/monitoring stability-related factors, in addition, to controlling impurities during the manufacturing process such as providing the ranitidine composition in a vacuum vial in which the air has been removed and hermetically sealed with a lid to prevent moisture/oxygen infiltration so as to provide a much lower amount of NDMA such as less than 160 ppb, less than 80 ppb, or less than 17 ppb. It was shown by Abe supra that the amount of NDMA during storage at 60°C/75% RH for 7 days can be optimize to an amount as low as about 200 ppb, thereby rendering obvious the claimed feature of “less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days,” by routinely controlling impurities during the manufacturing process and packaging so as to provide a storage stable ranitidine composition, and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim(s) 2, 14-16, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over of Sokol et al (Acta Poloniae Pharmaceutica—Drug Research, 2011, 68(2): 169-177; previously cited) in view of Abe et al (Chem. Pharm. Bull., 8 August 2020, 68: 1008-1012) and Pilgaonkar et al (US 2017/0128379 A1), and as evidenced by Niedzielski et al (Environ Sci Pollut Res., 2018, 25: 242-248).
Regarding claims 2, 14-16, and 22, Sokol teaches a pharmaceutical composition containing ranitidine HCl and trace amount of iron (Fe(II)) (Abstract; pages 169, right column to page 176, right column), thereby “trace amount” meets the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III).” It is noted that the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III)” encompassed a composition which can contain zero amount of iron (III), as “less than” would include no amount of the iron(III) and thus, trace amount of iron (Fe(II)) of Sokol stands to read on the claimed “less 1 ppm, less than 900 ppb, less than 600 ppb, or less than 300 ppb of iron(II) and iron (III).” Alternatively, the pharmaceutical composition of Sokol being produced using river water would contain a trace amount of both iron(II) and iron (III), as Sokol teaches the presence of metal ions that include but not limited to Fe(II) ions, and as evidenced by Niedzielski, river water naturally contains both iron(II) and iron (III) in their oxidized form (iron oxide) (Niedzielski: Abstract; pages 243-247).
While Sokol does not expressly teach the composition contains less than 160 ppb, less than 80 ppb, or less than 17 ppb of N-nitrosodimethylamine (NDMA) by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days” or “less than 320 ppb of NDMA by weight respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts when stored for 6 months at 40°C ± 2°C/75% RH ± 5%RH (Relative Humidity),” as recited in claims 2, 14, and 22, respectively, it would have been obvious to provide the composition of Sokol such that the composition is storage stable and contains amount of NDMA that is less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days or less than 320 ppb of NDMA by weight respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts when stored for 6 months at 40°C ± 2°C/75% RH ± 5%RH (Relative Humidity), per guidance from Abe.
Abe teaches that nitrosodimethylamine (NDMA) is a known impurity in ranitidine products during the manufacturing process and in high-temperature storage (Abstract; Introduction; pages 1010-1012). Abe teaches the FDA accepted daily intake limit for NDMA in ranitidine drug substance is 0.32 ppm (less than 320 ppb) (Abstract; pages 1010-1011). Abe highlights the risk of NDBA formulation in ranitidine formulations when extrapolated to storage under ambient conditions, and a force-degradation study under the stress condition (60°C for 1 week) strongly suggested that environmental factors such as moisture and oxygen are involved in the formation of NDMA in ranitidine formulation (Abstract; pages 1010-1011). Abe further teaches that storage of ranitidine tablets and reagent powders at high temperatures also increased the amount of nitrite, which is considered one of the factors influencing NDMA formations, and these data indicate that the necessity of controlling/monitoring stability-related factors, in addition, to controlling impurities during the manufacturing process, in order to provide stable ranitidine product by mitigating the safety risk of these products throughout their lifecycle (Abstract; pages 1010-1012). Abe showed that the amount of NDMA during storage at 60°C/75% RH in a vacuum vial, in which the air has been removed and hermetically sealed with a lid to prevent moisture/oxygen infiltration, was about 0.2 ppm (about 200 ppb) at Day 7 (Abstract; pages 1010-1012; Figs 2-4).
It would have been obvious to one of ordinary skill in art to provide the composition of Sokol such that the composition is storage stable and contains amount of NDMA that is less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days, or less than 320 ppb of NDMA by weight respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts when stored for 6 months at 40°C ± 2°C/75% RH ± 5%RH (Relative Humidity), and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because ordinary artisan knowing the drawbacks of NDMA impurities in ranitidine products during manufacturing process and storage per Abe would have looked to mitigating this NDMA impurities in the ranitidine composition Sokol by controlling/monitoring stability-related factors, in addition, to controlling impurities during the manufacturing process such as providing the ranitidine composition in a vacuum vial in which the air has been removed and hermetically sealed with a lid to prevent moisture/oxygen infiltration so as to provide a much lower amount of NDMA such as less than 160 ppb, less than 80 ppb, or less than 17 ppb. It was shown by Abe supra that the amount of NDMA during storage at 60°C/75% RH for 7 days can be optimize to an amount as low as about 200 ppb, thereby rendering obvious the claimed features of “less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days” or “less than 320 ppb of NDMA by weight respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts when stored for 6 months at 40°C ± 2°C/75% RH ± 5%RH (Relative Humidity),” by routinely controlling impurities during the manufacturing process and packaging so as to provide a storage stable ranitidine composition, and achieve Applicant’s claimed invention with reasonable expectation of success.
With respect to the chelating agent of claim 2, Pilgaonkar teaches a pharmaceutical composition comprising an active ingredient such as ranitidine, and at least one pharmaceutically acceptable excipient including stabilizers such as chelating agents ([0014]-[0032]; claim 4). It would have been obvious to one of ordinary skill in the art to include a chelating agent in the pharmaceutical composition containing ranitidine of Sokol in view of Abe, and produce the claimed invention. One of ordinary skill in the art would have been motivated do so because Pilgaonkar provided the guidance for including a chelating agent in a pharmaceutical composition containing an active ingredient such as ranitidine, as chelating agents are known pharmaceutically acceptable excipient conventionally added to pharmaceutical preparation to inhibit or prevent degradation of the drug during manufacturing process and over shelf life of the composition per Pilgaonkar ([0016]). Thus, an ordinary artisan seeking to further inhibit or prevent degradation of the ranitidine over shelf life of the composition, would have looked to including conventionally known pharmaceutically acceptable excipients including chelating agent in the pharmaceutical composition containing ranitidine of Sokol in view of Abe, and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 07/22/2026 have been fully considered but they are not persuasive.
Applicant’s arguments on pages 8-11 of the Remarks filed with 07/22/2026 respect to “Sokol in view of Parr and Winston,” “Sokol in view of Parr, Winston, and Pilgaonkar,” and unexpected results drawn to stability profile are not persuasive and moot in view of the new 103 rejections on pages 4-11 of this office action, which were necessitated by Applicant’s claim amendments.
Applicant’s arguments and the alleged unexpected results are not persuasive because as discussed above in the pending 103 rejections, it would have been obvious to one of ordinary skill in art to provide the composition of Sokol such that the composition is storage stable and contains amount of NDMA that is less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days. This is because an ordinary artisan knowing the drawbacks of NDMA impurities in ranitidine products during manufacturing process and storage per Abe (Abstract; pages 1010-1012; Figs 2-4) would have looked to mitigating this NDMA impurities in the ranitidine composition Sokol by controlling/monitoring stability-related factors, in addition, to controlling impurities during the manufacturing process such as providing the ranitidine composition in a vacuum vial in which the air has been removed and hermetically sealed with a lid to prevent moisture/oxygen infiltration so as to provide a much lower amount of NDMA such as less than 160 ppb, less than 80 ppb, or less than 17 ppb. It was shown by Abe supra that the amount of NDMA during storage at 60°C/75% RH for 7 days can be optimize to an amount as low as about 200 ppb, thereby rendering obvious the claimed feature of “less than 160 ppb, less than 80 ppb, or less than 17 ppb by weight with respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts after an exposure to 70°C for 5 days,” or “less than 320 ppb of NDMA by weight respect to the total dry weight of ranitidine or its pharmaceutically acceptable salts when stored for 6 months at 40°C ± 2°C/75% RH ± 5%RH (Relative Humidity),” by routinely controlling impurities during the manufacturing process and packaging so as to provide a storage stable ranitidine composition.
As a result, for at least the reason discussed above, claims 1-6, 14-16, and 22 remain rejected as being obvious and unpatentable over the combined teachings of the cited prior arts in the pending 103 rejections as set forth in this office action.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOAN THI-THUC PHAN whose telephone number is (571)270-3288. The examiner can normally be reached 8-5 EST Monday-Friday.
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, Brian Kwon can be reached at 571-272-0581. 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.
/DOAN T PHAN/ Primary Examiner, Art Unit 1613
