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 .
Status of Claims
The claim listing filed 21 May 2026 is pending. The amendment of claim 1, 2, 4-7, 14 and 16 are acknowledged. The withdrawal of claim 20 is acknowledged. The cancelation of claim 3 is acknowledged. Claims 1-2, 4-12 and 14-19 are being examined on the merits in this office action.
Specification
Response to Arguments: The objection to the specification has been withdrawn in view of the amendment to the specification flied 21 May 2026.
Claim Rejections - 35 USC § 112
Response to Arguments: The rejection of claim 3 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite regarding what “acetic acid at 0.1-0.25%” is meant to represent, has been withdrawn in view of the cancelation of claim 3 in the response filed 21 May 2026.
The rejection of claims 1-2, 4-12 and 14-19 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite regarding what “acetic acid at 0.1-0.25%” is meant to represent, has been withdrawn in view of the amendments filed 21 May 2026.
The rejection of claims 5, 10, and 11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite regarding what “any other cetrorelix impurity after storage” is meant to represent has been withdrawn in view of the amendments filed 21 May 2026.
Claim Rejections - 35 USC § 103
Response to Arguments: The rejection of claim 3 under 35 U.S.C. 103 as being unpatentable over Patel et al., hereafter “Patel”, (US20130303464A1), listed in the IDS filed 20 December 2024, in view of Izutsu (“Stabilization of therapeutic proteins by chemical and physical methods.” Methods Mol Biol. 2005;308:287-92. doi: 10.1385/1-59259-922-2:287. PMID: 16082042.) is now moot in view of the cancellation of claim 3 in the response filed 21 May 2026.
Claims 1-2, 4-12 and 15-19 were rejected under 35 U.S.C. 103 as being unpatentable over Patel et al., hereafter “Patel”, (US20130303464A1), listed in the IDS filed 20 December 2024, in view of Izutsu (“Stabilization of therapeutic proteins by chemical and physical methods.” Methods Mol Biol. 2005;308:287-92. doi: 10.1385/1-59259-922-2:287. PMID: 16082042.). The rejection regarding claims 1, 12, 15 and 17-19 is maintained. The rejection regarding 2, 4-11, 14 and 16 have been withdrawn in view of the amendments in the response filed 21 May 2026.
Claim 14 was rejected under 35 U.S.C. 103 as being unpatentable over Patel et al., hereafter “Patel”, (US20130303464A1), listed in the IDS filed 20 December 2024, and Izutsu (“Stabilization of therapeutic proteins by chemical and physical methods.” Methods Mol Biol. 2005;308:287-92. doi: 10.1385/1-59259-922-2:287. PMID: 16082042.), as applied to claim 1 above, and further in view of Breslyn, W "Net Ionic Equation for NaOH + CH3COOH" (2019). Applicants’ amendments, see page 2 of the amended claims filed 21 May 2026, have been fully considered. The rejection of claim 14 has been withdrawn.
Applicants’ remarks, see pages 1-3 of the response filed 21 May 2026, with respect to claims 1-2, 4-12 and 14-19, has been fully considered but they are not persuasive.
Applicants argue, in the response filed 21 May 2026, that the lowest amount of acetic acid that Patel formulated was 0.3%, as described in Example 1 at p. 3. Applicants also argue that Patel, the 0.3% acetic acid formulation had total impurities of 0.5% after one month, which is above the claimed concentration of less than 0.5% of only one impurity (deaminated cetrorelix) demonstrated and claimed in the instant application. Applicants also argue that “the skilled artisan would not believe that Patel establishes that less than the claimed 0.5% deaminated cetrorelix could be achieved. Additionally, by asserting that the composition in Example 1 of Patel is suitable for subcutaneous injection, the skilled artisan would believe that a total impurity level of 0.5% after one month, and as high as 1.59% after six months is suitable for subcutaneous injection. This is further supported by the data in Table 2 of the instant application (p. 3), which shows that a total impurity level of as high as 0.96% is present in a commercial lot of Cetrotide® at expiry. Applicant asserts that Izutsu is irrelevant to any of the amended claims because Izutsu is directed to stabilization of proteins with “delicate three-dimensional structures” (Izutsu, first full sentence) having secondary and tertiary structures, and not oligopeptides like cetrorelix, a decapeptide, much smaller than the 50 amino acid minimum size of a protein, five times the size of cetrorelix.” See pages 1-3 of the response filed 21 May 2026. The applicant’ arguments filed 21 May 2026 have been fully considered and were found unpersuasive.
In response to the applicants’ arguments that the cited Patel reference does not teach acetic acid at 0.1-0.25%w/v in the aqueous formulation, Patel teaches the low amounts of glacial acetic acid being 0.1% to 0.5% w/v of the preparation (pg. 2, para [0027] “According to the present invention, use of low amount of glacial acetic acid in the pharmaceutical preparation corresponds to around 0.1% w/v to 0.5% w/v of the said preparation.”). One of ordinary skill in the art would, with reasonable expectation of success, adjust the acetic acid concentration, as described in example 1 of Patel, to be any concentration around 0.1%-0.5% w/v due to Patel teaching that the range being a “low amount of acetic acid”. Regarding the argument that the 0.3% acetic acid formulation of Patel had total impurities of 0.5% after one month and that the Izutsu reference is irrelevant to the claims due it teaching the “stabilization of proteins” not cetrorelix, a decapeptide. Patel shows that after one month, the single max impurity is 0.24 and that when kept at 2-8°C, no aggregation was observed and that the single max impurity was 0.16 and the total impurity was 0.27 ([0056-0057] “No aggregation was observed on stability at 2-8°C. and 25°C./60% relative humidity for at least 6 months. Stability Data: (see table below)”).
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Regarding the argument that the Izutsu reference is irrelevant to the claims due it teaching the “stabilization of proteins”, Izutsu teaches that optimizing the environment of proteins increases their stabilization. One of ordinary skill in the art before the effective filing date would have a reasonably believe that keeping a preparation at a lower temperature and reducing additional stressors would result in more stable formulations (pg. 289 “Formulation types and excipients are selected to maximize the pharmaceutical quality of the product depending on the protein stability, clinical needs, and pharmaceutical acceptability. Aqueous formulations are the preferred choice because of the convenience of manufacturing and using them. Optimization of the protein formulations is attained by a combination of the following relevant experiments. 1. Obtain the protein stability profile through the analysis of protein solutions exposed to possible process- or storage-related stresses (e.g., high temperature and agitation).”).
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.
Claims 1, 12, 15 and 17-19 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al., hereafter “Patel”, (US20130303464A1), listed in the IDS filed 20 December 2024, in view of Izutsu (“Stabilization of therapeutic proteins by chemical and physical methods.” Methods Mol Biol. 2005;308:287-92. doi: 10.1385/1-59259-922-2:287. PMID: 16082042.).
In view of the amendment made in the response filed 21 May 2026, the following rejection of claims 1, 12, 15, and 17-19 is maintained.
Regarding claim 1, Patel teaches an aqueous formulation comprising cetrorelix and/or a salt thereof, an isotonicity adjuster, glacial acetic acid, and water, suitable for subcutaneous injection (pg. 2, para [0024]; “It has been found out surprisingly by the inventors of the present invention that a stable ready-to-use aqueous pharmaceutical preparation containing Cetrorelix or its pharmaceutically acceptable salt for parenteral administration, can be prepared by using low amounts of glacial acetic acid with Cetrorelix acetate, tonicity adjusting agent and optionally other pharmaceutically acceptable excipients in water.”; pg. 2, para [0026] “Pharmaceutical preparation according to the present invention is administered parenterally, wherein the preferred mode of parenteral administration is Subcutaneous administration.” ). Patel teaches the low amounts of glacial acetic acid being 0.1% to 0.5% w/v of the preparation (pg. 2, para [0027] “According to the present invention, use of low amount of glacial acetic acid in the pharmaceutical preparation corresponds to around 0.1% w/v to 0.5% w/v of the said preparation.”). Patel teaches that the pharmaceutical preparation is stable (no aggregation observed) when the preparation is kept at 25 °C for at least six months (pg. 3, para [0049] “According to the present invention, the said pharmaceutical preparation is stable; wherein “stable pharmaceutical preparation' is defined as no aggregation observed when the said pharmaceutical preparation is kept for stability studies carried out at 2° C. to 8°C. (Real time study) and 25° C./60% relative humidity (Accelerated study) for at least 6 months and wherein the assay of Cetrorelix would not be less than 90%.”).
Patel does not teach the aqueous formulation specifically comprising less than 0.5% deamidated cetrorelix after storage for at least one month at 25 °C.
Izutsu teaches that the alteration of protein structures via amino acid alteration and pH adjustment improve stability enough to meet shelf life requirements, even when being stored at low temperatures is not enough (pg. 287 “Aqueous solutions that are ready for injection are often the most convenient and preferable dosage forms for therapeutic proteins, whereas many purified proteins are not stable enough in the solutions to meet the shelf-life requirements, even when they are stored at low temperatures. Altering the protein structure (amino acid alternation and chemical modification) and altering the environment (e.g., pH change and dehydration) are two major methods to stabilize various proteins. Optimizing the protein environments by changing the physical state and/or use of excipients usually attains the stability of therapeutic proteins.”). Izutsu also teaches that formulation types and excipients that maximize pharmaceutical quality of products can be attained via a combination of solving stressors (temperature, agitation, etc.), adding pH buffers, tonicity adjustors and stabilizers.
Taking the teachings of Patel and Izutsu, a person of ordinary skill in the art would reasonably consider the addition of acetic acid, a lower temperature, and an isotonicity adjuster, as taught in Patel, to fall have the percentage of deamidated cetrorelix because routine optimization of variables found in the art is to be considered to be within the level of ordinary skill in the art. See MPEP §2144 (II). (“[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%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("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.")”).
Regarding the aqueous formulation comprising less than 0.5% deamidated cetrorelix after storage for at least one month at 25 °C, one of ordinary skill in the art would reasonably believe that through routine optimization (storage at 25 °C and 0.1-0.25% w/v of acetic acid), keeping an aqueous formulation at a lower temperature, combined with having an isotonicity adjuster and acetic acid would lead to lower cetrorelix degradation as stated in Patel.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify Patel’s teachings with Izutsu’s teachings because one of ordinary skill in the art would be inclined to believe that with standard routine optimization, the deamidation of cetrorelix would be low. Patel teaches the addition of an isotonicity adjuster, acetic acid, and water, and storage for at least one month at 25 °C.
One of ordinary skill in the art would have combined the two teachings and had a reasonable expectation of success because "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.".
Regarding claim 12, Patel further teaches the aqueous formulation wherein the isotonicity adjuster is mannitol (pg. 2, para [0037]; “Tonicity adjusting agents that can be included in the said pharmaceutical preparation comprise of mannitol, lactose, dextrose, or the likes thereof. Preferred tonicity adjusting agent for the said pharmaceutical preparation is mannitol.”).
Regarding claim 15, Patel further teaches the aqueous solution having a pH of about 2.5 to about 5 (pg. 2, para [0036]; “Further, according to the present invention, the pH of the said pharmaceutical preparation is in the range of 2.5 to 5…”).
Regarding claim 17, Patel further teaches aqueous formulation packaged in a syringe (pg. 3, para [0045]; “This sterile pharmaceutical preparation is filled in Suitable container/closure system, e.g., ampoules, vials, prefilled syringe system, etc.”).
Regarding claim 18, Patel further teaches aqueous formulation packaged in a vial (pg. 3, para [0045]; “This sterile pharmaceutical preparation is filled in Suitable container/closure system, e.g., ampoules, vials, prefilled syringe system, etc.”).
Regarding claim 19, Patel further teaches aqueous formulation having a cetrorelix concentration of 0.20-0.30 mg/mL (pg. 2, para [0023]; “Present invention relates to a stable ready-to-use aqueous pharmaceutical preparation of Cetrorelix or its pharmaceutically acceptable salt for parenteral administration, wherein the said preparation does not comprise of a surfactant and wherein the concentration of Cetrorelix is 0.25 mg/ml…”).
Claims 2, 4-11, 14 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al., hereafter “Patel”, (US20130303464A1), listed in the IDS filed 20 December 2024, in view of Izutsu (“Stabilization of therapeutic proteins by chemical and physical methods.” Methods Mol Biol. 2005;308:287-92. doi: 10.1385/1-59259-922-2:287. PMID: 16082042.).
The following rejections are new as necessitated by the amendment of claims 2, 4-11, 14 and 16, submitted in the response filed 21 May 2026.
Regarding claim 2, Patel teaches an aqueous formulation comprising cetrorelix and/or a salt thereof, an isotonicity adjuster, glacial acetic acid, and water, suitable for subcutaneous injection (pg. 2, para [0024]; “It has been found out surprisingly by the inventors of the present invention that a stable ready-to-use aqueous pharmaceutical preparation containing Cetrorelix or its pharmaceutically acceptable salt for parenteral administration, can be prepared by using low amounts of glacial acetic acid with Cetrorelix acetate, tonicity adjusting agent and optionally other pharmaceutically acceptable excipients in water.”; pg. 2, para [0026] “Pharmaceutical preparation according to the present invention is administered parenterally, wherein the preferred mode of parenteral administration is Subcutaneous administration.” ).
Regarding the limitation of it being stored for at least 15 months at 2-8°C, one of ordinary skill in the art would reasonably believe that through routine optimization (storage at 2-8°), keeping an aqueous formulation at a lower temperature, combined with having an isotonicity adjuster and acetic acid would lead to formulation preservation for an extended period of time.
Regarding claims 4-11, 14 and 16, the combined teachings of Patel and Izutsu show that by using routine optimization (changing temperature, etc.), it would be obvious to one of ordinary skill in the art that the lower the temperature, the lower the degradation. See Supra (claim 1). Patel also shows that when the formulation is kept at 2-8°C, no aggregation was observed and that the single max impurity was 0.16 and the total impurity was 0.27 ([0056-0057] “No aggregation was observed on stability at 2-8°C. and 25°C./60% relative humidity for at least 6 months. Stability Data: (see table below)”).
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One of ordinary skill in the art before the effective filing date of the instant invention would be motivated to take the teachings of Patel and Izutsu and reasonably consider the addition of acetic acid, a lower temperature, and an isotonicity adjuster, as taught in Patel, and attempt to keep the solution at a lower temperature to reduce impurities due to Patel showing that when kept at 2-8°C, no aggregation was observed and that the single max impurity was 0.16, this consideration is routine optimization of variables found in the art and is to be considered to be within the level of ordinary skill in the art. See MPEP §2144 (II). (“[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%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("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.")”).
Status of Claims
Claims 1-2, 4-12 and 14-19 are rejected under 35 U.S.C. 103.
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Daliyah M. Brown whose telephone number is (571)272-0136. The examiner can normally be reached Monday-Thursday 9:00 am - 4:30 pm.
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/Daliyah M. Brown/Examiner, Art Unit 1654
/LIANKO G GARYU/Supervisory Patent Examiner, Art Unit 1654
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