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 .
Amendment after Non-final office action filed on November 17, 2025 is acknowledged.
Claims 1-10 are pending in this application.
Withdrawn Objections and Rejections
Objection to the abstract is hereby withdrawn in view of Applicant’s amendment to the abstract.
Objection to the TITLE is hereby withdrawn in view of Applicant’s amendment to the TITLE.
Objection to claim 1 is hereby withdrawn in view of Applicant’s amendment to the claim.
Objection to claim 4 is hereby withdrawn in view of Applicant’s amendment to the claim.
Rejections of claims 1-10 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, are hereby withdrawn in view of Applicant’s amendment to the claims.
Maintained Rejections
35 U.S.C. 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-4, 6 and 8-9 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al (US 2013/0303464, filed with IDS) in view of Jorgensen et al (Informa Healthcare, 2009, 1219-1230, filed with IDS) or Parkins et al (Reviews Research Focus, 2000, 3(4): 129-134, filed with IDS).
14. Patel et al teach stable ready-to-use 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 (see for example, paragraph [0024]), meeting the limitation of instant claims 1 and 6, in part. Patel et al teach that the concentration of Cetrorelix is 0.25 mg/ml or more and has a pH in between 2.5 to 5 (see paragraph [0025]). Patel et al further teach that the preferred concentration of Cetrorelix is in a range of 0.25 to 0.75 mg/ml, more preferably in a range of 0.25 to 0.5 mg/ml…(see paragraph [0035]), and the pH of the said pharmaceutical preparation is in the range of 2.5 to 5; preferably in the range of 2.8 to 3.5 (see paragraph [0036]), meeting the limitation of instant claim 1, in part. Patel et al further teach that the pharmaceutical preparation comprise tonicity adjusting agents; tonicity adjusting agents decrease the hemolysis of blood cells and reduce pain and irritation at the injection site. 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 is mannitol (see paragraph [0037]), meeting the limitation of instant claims 1 ad 3-4, in part. Additionally, Patel et al teach that the amounts of tonicity adjusting agent used in the preparation is adjusted to obtain osmolality of the preparation in the range of 290 to 330 mOsm/Kg (see paragraph [0038]), meeting the limitation of instant claims 1 and 3, in part. Patel et al teach that the 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 preparation (see paragraph [0027]). Patel et al teach that the pharmaceutical preparation is administered parenterally…is subcutaneous administration (see paragraph [0026]), meeting the limitation of instant claim 8, in part. Patel et al further teach the following:
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(see Exanple 1, for example). The ratio range of Cetrorelix to acidifying agent of 0.01: 1 to about 1:1 recited in instant claim 2 and the shelf life recited in instant claim 9 are met.
Additionally, instant claim 9 recites the inherent property of the ready-to-use pharmaceutical composition. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).”
The difference between Patel et al and instant claims is that the reference does not teach glycine in the composition.
15. However, Jorgensen et al teach that the glycine is an excipient known to stabilize macromolecules such as peptides and proteins (see Table 1, for example). Parkins et al also teach that glycine is an excipient known to stabilize macromolecules (see p. 134, right column, Box 1). Parkins et al further teach that amino acids have been added to biopharmaceuticals for a variety of reasons…glycine, arginine and lysine have been reported to prevent aggregation…amino acids have been found to be useful as chelating agents, and may reduce surface adsorption (see p. 135, left column, “Amino acids”).
16. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Patel et al, Jorgensen et al and Parkins et al to add in glycine and additional known excipients that are known to stabilize macromolecules such as peptide and proteins. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Jorgensen et al and Parkins et al teach that amino acids have been added to biopharmaceuticals for a variety of reasons, for example, glycine, arginine and lysine have been reported to prevent aggregation. Therefore, one of ordinary skill in the art would expect the addition of glycine would stabilize the cetrorelix ready-to-use composition. Therefore, the combined art is prima facie obvious over instant claims 1-4, 6 and 8-9.
Please note: Claim 1v) recites an optional cosolvent. The broadest reasonable interpretation of instant claim 1, the cosolvent is not required for the stable ready-to-use pharmaceutical composition.
Response to Applicant’s Arguments
17. Applicant argues:
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18. Applicant’s arguments have been fully considered but are not found persuasive. Instant claims are drawn to a product invention, not a method of making the product. Additionally, instant rejection is an obviousness type rejection (35 U.S.C. 103). Patel et al explicitly teach a stable ready-to-use pharmaceutical preparation comprising Cetrorelix or its pharmaceutically acceptable salt for parenteral administration, with low amounts of glacial acetic acid, tonicity adjusting agent and other pharmaceutically acceptable excipients in water. Patel et al teach that the concentration of Cetrorelix is 0.25 mg/ml or more and has a pH between 2.5 to 5, tonicity adjusting agents that is mannitol, lactose, dextrose, or the likes thereof (the tonicity adjusting agent is mannitol), wherein the tonicity adjusting agent used in the preparation is adjusted to obtain osmolality of the preparation in the range of 290 to 330 mOsM/Kg, and the amount of glacial acetic acid about 0.1% w/v to 0.5% w/v of the preparation. Example 1 of Patel et al teach the ratio range of Cetrorelix to acidifying agent of 0.01:1 to about 1:1. Although the preparation of Patel et al do not comprise a glycine, it is well known in the art that glycine and other amino acids are known excipient that stabilize macromolecules such as peptides and proteins (see Jorgensen et al and Parkins et al). Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings and add in glycine and additional excipients that are known to stabilize macromolecules in the composition. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Jorgensen et al and Parkins et al teach that amino acids have been added to biopharmaceuticals for a variety of reasons, for example, glycine, arginine and lysine have been reported to prevent aggregation. Therefore, one of ordinary skill in the art would expect the addition of glycine would stabilize the cetrorelix ready-to-use composition. The combined art is prima facie obvious over instant claims 1-4, 6 and 8-9. Therefore, the rejection is deemed to be proper and is maintained herein.
19. Claim(s) 1-10 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Bauer et al (US Patent No. 7718599) in view of Patel et al (US 2013/0303464, filed with IDS), Jorgensen et al (Informa Healthcare, 2009, 1219-1230, filed with IDS) or Parkins et al (Reviews Research Focus, 2000, 3(4): 129-137, filed with IDS) and Pedersen et al (US Patent No. 8114833, cited in the previous office action).
20. Bauer et al teach a pharmaceutical composition for parenteral administration, comprising cetrorelix acetate in a concentration of 2.5 mg/ml and a pharmaceutically acceptable acid selected from a group of gluconic acid, glucaric acid or galactouronic acid, with pH of 2.5, 2.6, 3.1, 3.7 or 4.5, which helps in suppressing aggregation of cetrorelix acetate (see claim 1, for example). Bauer et al teach that the pharmaceutical composition comprises an excipient, wherein the excipient comprises gluconic acid, glucuronic acid…citric acid, ascorbic acid, or an amino acid (see claim 3). Bauer et al further teach that the excipient comprises polyethylene glycol (see claims 4-5, for example), wherein the excipient comprises cyclodextrins or its derivatives or sugar alcohols (see claim 6), wherein the sugar alcohol is mannitol (see claim 11), wherein the pharmaceutical composition for parenteral administration is an injection preparation (see claim 12), wherein the injection preparation is for subcutaneous injection (see claim 13), wherein the excipient is independently selected from mannitol, polyethylene glycol…glycine, citric acid and cyclodextrin (see claim 14).
The difference between the reference and instant claims is that the reference does not teach 0.1 mg/ml to 0.5 mg/ml cetrorelix base or a pharmaceutically acceptable salt thereof, the amount of glycine in the range of about 1 mg/ml to about 10 mg/ml, and the propylene glycol as the cosolvent.
21. However, Patel et al teach stable ready-to-use pharmaceutical preparation containing Cetrorelix or its pharmaceutically acceptable slat 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 (see for example, paragraph [0024]). Patel et al teach that the concentration of Cetrorelix is 0.25 mg/ml or more and has a pH in between 2.5 to 5 (see paragraph [0025]). Patel et al further teach that the preferred concentration of Cetrorelix is in a range of 0.25 to 0.75 mg/ml, more preferably in a range of 0.25 to 0.5 mg/ml…(see paragraph [0035]), and the pH of the said pharmaceutical preparation is in the range of 2.5 to 5; preferably in the range of 2.8 to 3.5 (see paragraph [0036]). Patel et al further teach that the pharmaceutical preparation comprise tonicity adjusting agents; tonicity adjusting agents decrease the hemolysis of blood cells and reduce pain and irritation at the injection site. 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 is mannitol (see paragraph [0037]). Additionally, Patel et al teach that the amounts of tonicity adjusting agent used in the preparation is adjusted to obtain osmolality of the preparation in the range of 290 to 330 mOsm/Kg (see paragraph [0038]). Patel et al teach that the 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 preparation (see paragraph [0027]). Patel et al teach that the pharmaceutical preparation is administered parenterally…is subcutaneous administration (see paragraph [0026]). Patel et al further teach the following:
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(see Example 1, for example). The ratio range of Cetrorelix to acidifying agent of 0.01: 1 to about 1:1 recited in instant claim 2 and the shelf life recited in instant claim 9 are taught.
Additionally, instant claim 9 recites the inherent property of the ready-to-use pharmaceutical composition. The MPEP § 2112 states: “Once a reference teaching product appearing to be substantially identical is made the basis of a rejection, and the Examiner presents evidence or reasoning tending to show inherency, the burden shifts to the Applicant to show an unobvious difference ‘[t]he PTO can require an Applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his [or her] claimed product. Whether the rejection is based on inherency’ under 35 U.S.C. 102, on prima facie obviousness’ under 35 U.S.C. 103, jointly or alternatively, the burden of proof is the same...[footnote omitted].” The burden of proof is similar to that required with respect to product-by-process claims. In re Fitzgerald, 619 F.2d 67, 70, 205 USPQ 594, 596 (CCPA 1980) (quoting In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433-34 (CCPA 1977)).”
22. Jorgensen et al teach that the glycine is an excipient known to stabilize macromolecules such as peptides and proteins (see Table 1, for example). Parkins et al also teach that glycine is an excipient known to stabilize macromolecules (see p. 134, right column, Box 1). Parkins et al further teach that amino acids have been added to biopharmaceuticals for a variety of reasons…glycine, arginine and lysine have been reported to prevent aggregation…amino acids have been found to be useful as chelating agents, and may reduce surface adsorption (see p. 135, left column, “Amino acids”).
23. Furthermore, Pedersen et al teach a pharmaceutical formulations comprising a peptide and propylene glycol (see abstract, for example). Pedersen et al teach different concentration of propylene glycol (from 1 mg/ml to about 100 mg/ml) in the pharmaceutical composition (see claim 1), from about 1 mg/ml to about 50 mg/ml (see claim 2), about 5 mg/ml to about 25 mg/ml (see claim 3), from about 8 mg/ml to about 16 mg/ml (see claim 4). Pedersen et al further teach that “due to the ability of propylene glycol to reduce clogging of injection devices when compared to other isotonic agents and to mannitol in particular, in a preferred embodiment, the formulations of the invention are to be administered parenterally to a patient in need thereof…may be performed by subcutaneous, intramuscular or intravenous injection…” (see column 13, lines 43-51). Pedersen et al additionally teach that the formulation may further comprise a stabilizer selected from the group…polyethylene glycol (e.g. PEG 3350)…different salts (e.g. sodium chloride), L-glycine, L-histidine…(see column 11, lines 27-39, for example).
24. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Bauer et al, Patel et al, Jorgensen et al or Parkins et al and Pedersen et al, since all references teach biopharmaceutical compositions comprising proteins. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Patel et al teach that smaller amounts/concentrations of cetrorelix acetate in glacial acetic acid at pH between 2.5 to 5 also had absence of formation of aggregates of cetrorelix acetate, Jorgensen et al and Parkins et al teach that amino acids have been added to biopharmaceuticals for a variety of reasons, for example, glycine, arginine and lysine have been reported to prevent aggregation. Furthermore, Pedersen et al teach that propylene glycol reduces clogging of injection devices when compared to other isotonic agents, one of ordinary skill in the art would be motivated to use propylene glycol as a cosolvent in injection formulations for better administration. Therefore, one of ordinary skill in the art would expect the addition of glycine would stabilize the cetrorelix ready-to-use composition and propylene glycol to reduce clogging of the formulation. Furthermore, in regards to the different concentrations of each components in the ready-to-use formulation, one of ordinary skill in the art would be motivated to optimize the concentrations of already known components for optimal formulation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). One of ordinary skill in the art would have a reasonable expectation of success, since “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”.
Therefore, the combined art is prima facie obvious over instant claims 1-10.
Response to Applicant’s Arguments
25. Applicant argues that:
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26. Applicant’s arguments have been fully considered but are not found persuasive.
Instant claims are drawn to a product invention, not a method of making the product. Additionally, instant rejection is an obviousness type rejection (35 U.S.C. 103). Bauer et al explicitly teach a pharmaceutical composition for parenteral administration, comprising cetrorelix acetate in a concentration of 2.5 mg/ml and a pharmaceutically acceptable acid selected from a group of gluconic acid, glucaric acid or galactouronic acid, with pH of 2.5, 2.6, 3.1, 3.7 or 4.5, which helps in suppressing aggregation of cetrorelix acetate. Bauer et al teach that the pharmaceutical composition comprises an excipient, wherein the excipient comprises gluconic acid, glucuronic acid…citric acid, ascorbic acid, or an amino acid and that the excipient comprises polyethylene glycol wherein the excipient comprises cyclodextrins or its derivatives or sugar alcohols, the sugar alcohol is mannitol and the pharmaceutical composition is for parenteral administration, and is an injection preparation for subcutaneous injection. Bauer et al teach that the excipient is independently selected from mannitol, polyethylene glycol…glycine, citric acid and cyclodextrin.
As described above in the rejection, Patel et al teach a stable ready-to-use pharmaceutical composition comprising Cetrorelix or its pharmaceutically acceptable salt for parenteral administration in the amounts, osmolality and pH of instant claims.
Although the preparation of Patel et al do not comprise a glycine, it is well known in the art that glycine and other amino acids are known excipient that stabilize macromolecules such as peptides and proteins (see Jorgensen et al and Parkins et al). Pedersen et al teach a pharmaceutical formulations comprising a peptide and propylene glycol, and different concentrations of propylene glycol. Pedersen et al teach that propylene glycol reduces clogging of injection devices when compared to other isotonic agents. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings and add in glycine and additional excipients that are known to stabilize macromolecules in the composition. Additionally, one it would have been obvious to one of ordinary skill in the art to add in the propylene glycol to reduce any clogging in the injection devices, knowing that propylene glycol reduces clogging. One of ordinary skill in the art would be motivated to combine with a reasonable expectation of success, since Jorgensen et al and Parkins et al teach that amino acids have been added to biopharmaceuticals for a variety of reasons, for example, glycine, arginine and lysine have been reported to prevent aggregation. Additionally, one of ordinary skill in the art would be motivated to combine propylene glycol with a reasonable expectation that adding propylene glycol may reduce clogging of injection devices. Therefore, one of ordinary skill in the art would expect the addition of glycine would stabilize the cetrorelix ready-to-use composition, and addition of propylene glycol would reduce any clogging of the injection devices.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., ready-to-use aqueous composition of Cetrorelix that is manufactured as a sterile liquid solution without any lyophilization followed by a reconstitution step) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The combined art is prima facie obvious over instant claims 1-10. Therefore, the rejection is deemed to be proper and is maintained herein.
CONCLUSION
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 JULIE HA whose telephone number is (571)272-5982. The examiner can normally be reached Monday-Thursday 5:00 am- 6:30 pm EST.
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/JULIE HA/Primary Examiner, Art Unit 1654
12/04/2025
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