DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 1-14 and 18-21 are pending. Claims 15-17 are canceled.
3. Claims 1-14 and 18-21 are under examination.
Priority
4. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 8/2/2022, 12/21/2022, 6/7/2023, 1/31/2024 and 11/17/2025 have been considered by the examiner.
Claim Objections
6. Claims 20 and 21 are objected to because the claims do not recite a subject to be treated and to be administered with the composition.
Claim Rejections - 35 USC § 112
7. 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.
8. Claims 5, 8 and 9 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, 8 and 9, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(c) and/or (d).
Claim Rejections - 35 USC § 102
9. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
10. Claims 1-3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sharma et al (WO 2018/204368A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
Regarding claims 1 and 3, Sharma et al. teaches a liquid anti-human PD-1 antibody formulation comprising:
(a) about 125 to 175 mg/ml anti-human PD-1 antibody;
(b) about 3% to 5% mannitol (which corresponds to 165-275 mM mannitol) (a sugar alcohol) as a stabilizer;
(c) about 0.01% to 0.04% polysorbate 80 (a non-ionic surfactant); and
(d) about 8-12 mM histidine buffer (claim 29).
Regarding claim 2, Sharma et al. teaches that in some embodiments, the buffer is histidine at a pH of about 5 to about 6, in some embodiments, the buffer is L-histidine buffer (page 28, lines 17-18, page 31, line 27), and L-histidine and/or L-histidine hydrochloride at 10 mM is expected to maintain buffering capacity at the intended pH of the formulation tested (page 73, line 27).
Regarding trehalose recited in claim 1, Sharma et al. teaches that about 6%-8% trehalose (corresponding to 175-234 mM trehalose) can be used as a stabilizer (page 31, lines 14-16).
11. Claims 1, 3-5, 8-12 and 20-21 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cao et al. (WO 2018/028383A1, pub. date: 2/15/2018, IDS filed on 8/2/2022).
Regarding claims 1, 3-5 and 8-12, Cao et al. teaches a pharmaceutical composition comprising
(a) an anti-PD-I antibody at a concentration in the range of about 5-15 mg/mL,
(b) citrate at a concentration of about 15 mM to about 25 mM,
(c) histidine at a concentration of about 20 mM to about 30 mM,
(d) mannitol at a concentration of about 130 mM to about 165 mM,
(e) polysorbate 20 or polysorbate 80 (a non-ionic surfactant) at a concentration in the range of about 0.01 % to about 0.03% (corresponding 0.1-0.3 mg/ml), and
pH of about 5.5 to about 6.5 (claims).
Note that the pharmaceutical composition does not comprise pentetic acid.
Regarding claims 20 and 21, Cao et al. teaches a method of treating cancer in a subject comprising administering to the subject the above pharmaceutical composition (claim 13), wherein the cancer is melanoma (page 7).
12. Claims 1, 3-10, 12, 14 and 20-21 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Neelon et al. (WO 2021/126657A1, pub. date: 6/24/2021, effectively filed date: 12/18/2019).
Regarding claims 1, 3-9, 12 and 14, Neelon et al. discloses a pharmaceutical formulation comprising:
(a) an anti-PD-1 antibody at about 20 mg/mL to about 125 mg/mL,
(b) citrate buffer or histidine buffer at about 10 mM to about 40 mM,
(c) trehalose at about 2 to about 10% w/v (corresponding to 58-292 mM trehalose),
(d) polysorbate 80 at about 0.01% to about 0.1% w/v (corresponding to 0.1 mg/ml to 1 mg/ml polysorbate 80), at a pH of about 5.5 to about 6.5 (page 4, last para),
wherein the anti-PD-1 antibody is an anti-human PD-1 antibody (page 12, line 26).
Note that the formulation does not contain pentetic acid.
Regarding claim 10, Neelon et al. teaches that the pharmaceutical formulation may include mannitol or sorbitol (page 50, line 33)
Regarding claims 20-21, Neelon et al. teaches a method of treating cancer comprising administering to a subject in need thereof the above formulation, wherein the cancer is melanoma (page 5, lines 12-13 and page 60).
13. Claims 1-14 and 20-21 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Desai al (WO 2018/204374A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
Regarding claims 1-9, 12 and 14, Desai et al. discloses a liquid co-formulation comprising:
(a) about 10-120 mg/ml anti-LAG3 antibody and about 10-120 mg/ml anti-PD-1 antibody;
(b) about 30-120 mg/ml of a non-reducing disaccharide or polyol;
(c) about 0.05-2 mg/mL polysorbate 80 or 20;
(d) a buffer at pH about 5.8-6 (page 40, lines 18-40, page 41, lines 5-9),
wherein the buffer is histidine or L-histidine or citrate at 5-30 mM (page 30, lines 14-15 and page 37, line 10, page 38, lines 10-12),
the non-reducing disaccharide is sucrose or trehalose at a concentration of 50-90 mg/ml (corresponding to 146-263 mM) (page 31, lines 1-7).
Note that the formulation does not contain pentetic acid.
Regarding claims 10-11, Desal et al. teaches that the polyol is mannitol at a concentration of 10-50 mg/ml (corresponding to 82-275 mM) (page 31, lines 8-15)
Regarding claim 13, Desai teaches that anti-PD-1 antibody is pembrolizumab (pages 23-24 and page 27, line 33).
Regarding claims 20-21, Desai et al. teaches a method of treating cancer comprising administering to a subject in need thereof the above formulation, wherein the cancer is melanoma (page 3, lines 32-34, page 8, line 23).
Claim Rejections - 35 USC § 103
14. 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.
15. Claims 1-14 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al (WO 2018/204368A1, pub. date: 11/8/2018, IDS filed on 8/2/2022), in view of Desai al (WO 2018/204374A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
The teachings of Sharma et al. have been set forth above as they apply to claims 1-3.
Regarding claims 4-14 and 18-19, Sharma et al. teaches a liquid anti-human PD-1 antibody formulation comprising:
(a) an anti-human PD-1 antibody;
(b) about 3% to 8% sucrose (corresponding to 88-234 mM)
(c) about 0.01% to 0.04% polysorbate 80 (a non-ionic surfactant) (corresponding to 0.1-0.4 mg/ml polysorbate 80); and
(d) about 8-12 mM histidine buffer (claim 29),
wherein the concentration of the anti-human PD-1 antibody is 25 mg/ml (claim 7) and the anti-human PD-1 antibody is pembrolizumab (claim 38).
Sharma et al. teaches that sucrose, trehalose or mannitol can be used as stabilizer, trehalose is used at a concentration of about 6%-8% (corresponding to 175-234 mM trehalose) (page 25, lines 15-20, page 26, line 3, and page 31, lines 14-16), mannitol is used at about 5% w/v (corresponding to 275 mM) (page 2, line 15).
Sharma et al. further teaches that either histidine or citrate buffer can be used as buffer to control pH in the range of 5 to 6, 5.3 to 5.8 (page 28, lines 13-16).
Sharma et al. teaches that the formulation may be provided as a lyophilized powder and is reconstituted with water for injection (page 37, lines 22-26)
Regarding claim 20-21 Sharma et al. further teaches treating cancer by administering the formulation to a subject having cancer, wherein the cancer is melanoma (page 7, line 9-10 and page 10, line 8).
Sharma et al. does not specifically teaches that concentration of the citrate is 10 mM).
Desai et al. discloses that histidine or L-histidine or citrate can be used in making a formulation comprising an anti-human PD-1 antibody including pembrolizumab, wherein the concentration of citrate is 10 mM (page 30, lines 14-15).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted citrate buffer for histidine buffer in the formulation of Sharma in view of Desai. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16), and Desai et al. discloses that histidine or L-histidine or citrate can be used in making a formulation comprising an anti-human PD-1 antibody including pembrolizumab, and the concentration of citrate is 10 mM (page 30, lines 14-15).
Although Sharma and Desai do not specifically teach that the trehalose or sucrose is 205 mM. The concentration of 205 mM falls within the range of 175-234 mM trehalose or 88-234 mM of sucrose taught by Sharma. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have used different concentrations of trehalose or sucrose within the prior art range, including 205 mM for the purpose of finding an optimum or workable concentration to use in the claimed formulation.
MPEP 2144.05 states:
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).
Double Patenting
16. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
17. Claims 1-14 and 18-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 18-25 of copending Application No. 18/573,798 (reference application), in view of Sharma et al (WO 2018/204368A1, pub. date: 11/8/2018, IDS filed on 8/2/2022).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-12 and 18-25 of copending Application No. 18/573,798 (reference application) disclose a liquid pharmaceutical composition comprising: (a) an anti-human PD 1 antibody; (b) one or more amino acids other than histidine; (c) a non-ionic surfactant; and (d) citrate buffer, and water for injection and having a pH of 5.0 to 5.8,
wherein the citrate buffer is present in a concentration of 5 mM or 10 mM,
the non-ionic surfactant is polysorbate 20 or polysorbate 80 and is present in a concentration of 0.1 mg/ml to 0.4 mg/ml; preferably of 0.2 mg/ml,
the anti-human PD 1 antibody is pembrolizumab and is present in a concentration of 25 to 80 mg/ml; preferably of 25 mg/ml, and
wherein the one or more amino acids other than histidine is arginine and/or lysine.
The claims of copending application further disclose a method for treating a subject having cancer, comprising administering to the subject the pharmaceutical composition, wherein the cancer is melanoma, non-small cell lung carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, small cell lung cancer, microsatellite instability-high or mismatch repair deficient cancer, primary mediastinal large B- 155526745.1 4 cell lymphoma, gastric or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, Merkel cell carcinoma, endometrial carcinoma, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer or cervical cancer.
The claims of copending application disclose use one or more amino acids other than histidine, such as arginine or lysine as a stabilizer. The claims of copending application do not disclose using sugar such as sucrose or trehalose, or sugar alcohol such as mannitol as stabilizer, and using L-histidine as buffer.
Sharma et al. teaches that sucrose or trehalose, mannitol, arginine or glycine can be used as stabilizer in the formulation of anti-human PD-1 antibody (page 18, lines 26-27). Sharma et al. teaches using about 3% to 5% mannitol (which corresponds to 165-275 mM mannitol) (a sugar alcohol) as a stabilizer, about 6%-8% trehalose (corresponding to 175-234 mM trehalose) as a stabilizer (page 31, lines 14-16). Sharma et al. further teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16). Sharma et al. teaches that in some embodiments, the buffer is histidine at a pH of about 5 to about 6, in some embodiments, the buffer is L-histidine buffer (page 28, line 18, page 31, line 27).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted sucrose, trehalose or mannitol or arginine and/or lysine in the formulation of the copending application in view of Sharma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that sucrose or trehalose, mannitol, arginine or glycine can be used as stabilizer in the formulation of anti-human PD-1 antibody (page 18, lines 26-27), the concentration of mannitol is about 3% to 5% mannitol (which corresponds to 165-275 mM mannitol), the concentration of trehalose is about 6%-8% trehalose (corresponding to 175-234 mM trehalose) (page 31, lines 14-16).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the formulation of the copending application to use L-histidine as a buffer in view of Sharma. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success because Sharma et al. teaches that the buffer can be either histidine or citrate buffer (page 28, lines 13-16), specifically the buffer is histidine at a pH of about 5 to about 6, or L-histidine buffer (page 28, line 18, page 31, line 27).
Although the claims of copending application and Sharma do not specifically disclose that the trehalose or sucrose is 205 mM. The concentration of 205 mM falls within the range of 175-234 mM trehalose taught by Sharma. It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention to have used different concentrations of trehalose or sucrose within the prior art range, including 205 mM for the purpose of finding an optimum or workable concentration to use in the claimed formulation.
MPEP 2144.05 states:
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).
Conclusion
18. No claims are allowed.
19. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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/HONG SANG/Primary Examiner, Art Unit 1646