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 .
The preliminary amendment filed 11/22/22 is acknowledged. Claims 1, 7, 8 have been amended. Claims 24-26 have been added. Claims 1-26 are pending and under examination.
Claim Objections
Claim 1 is objected to because of the following informalities: The claim contains the acronym GLP-1. While acronyms are permissible shorthand in the claims, the first recitation should include the full recitation of the term followed by the acronym in parentheses. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
The instant claims are drawn to a liquid formulation of a peptide conjugate, wherein the liquid formulation comprises: 18 nmol/mL to 940 nmol/mL of a peptide conjugate of Chemical Formula 1 below; a buffering agent in an amount for maintaining the pH of the liquid formulation in the range of 4.5 to 7.5; 1% (w/v) to 20% (w/v) of a saccharide; and 0.0010% (w/v) to 0.2% (w/v) of a nonionic surfactant: [Chemical Formula 1]
PNG
media_image1.png
270
684
media_image1.png
Greyscale
in Chemical Formula 1 above, Q is a peptide of General Formula 1 below; Z is an immunoglobulin Fc fragment; and n is a natural number, wherein the value of n is determined such that the average molecular weight of the [OCH2CH2]n region in the peptide conjugate is 10 kDa; [General Formula 1] His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Xaa 12-Tyr-Leu-Asp-Xaa 16-Lys-Arg- Ala-Xaa20-Glu-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Cys (SEQ ID NO: 1), in General Formula 1 above, Xaa2 is 2-aminoisobutyric acid (Aib), Xaa12 is lysine (K), Xaa16 is glutamic acid (E), Xaa20 is lysine (K); and a lactam ring may or may not be formed between Xaa12 and Xaa16 or Xaa16 and Xaa20 residues.
The claims broadly encompass a genus of formulations comprising a peptide conjugate, a buffering agent in an amount for maintaining the pH of the liquid formulation in the range of 4.5-7.5, a saccharide, and a nonionic surfactant. The specification teaches that the term "buffer" refers to a buffering system and the buffering agent of system serves to maintain the pH of the liquid formulation. The specification teaches that any buffering agent capable of maintaining a pH that can stabilize the peptide conjugate of Chemical Formula 1, which is the target material for stabilization, may be used without limitation. The specification teaches that the buffering agent may be a pH buffer, including phosphoric acid and a conjugate alkali salt thereof (e.g., phosphate: sodium phosphate, potassium phosphate, or a hydrogen or dihydrogen salt thereof), citric acid and a salt thereof (e.g., sodium citrate), acetic acid and a salt thereof (e.g., sodium acetate), or histidine and a salt thereof, and a mixture of these buffers may also be used, but the buffering agent is not limited thereto. The specification teaches that the saccharide, which is one component included in the liquid formulation of the present invention, refers to monosaccharides, disaccharides, polysaccharides, oligosaccharides, etc., and can increase the stability of the long-acting conjugate of the peptide having activities for a glucagon receptor and a GLP-1 receptor component in a solution that allows the solution to resist changes in pH, and buffers include, for example, acetate, citrate, succinate, and histidine. The specification teaches that the nonionic surfactant he nonionic surfactant, which is one component included in the liquid formulation, lowers the surface tension of the protein solution, thereby preventing protein adsorption or aggregation on the hydrophobic surface. Specific examples of the nonionic surfactant that can be used in the present invention may include polysorbates (e.g., polysorbate 20(polyoxyethylene (20)sorbitan monolaurate), polysorbate 40(polyoxyethylene (20)sorbitan monopalmitate), polysorbate 60(polyoxyethylene (20)sorbitan monostearate), polysorbate 80(polyoxyethylene (20) sorbitan monooleate); the numerical value 20 after the polyoxyethylene group means the total number of oxyethylene groups -(CH2CH2O)-), poloxamer (PEO-PPO-PEO copolymer; PEO: poly(ethylene oxide), PPO: poly(propylene oxide)), polyethylene-polypropylene glycol, polyoxyethylene compounds (e.g., polyoxyethylene-stearate, polyoxyethylene alkyl ethers (alkyl: C1-C30),polyoxyethylene monoallyl ether, alkylphenyl polyoxyethylene copolymer (alkyl: C1-C30), etc.), sodium dodecyl sulfate (SDS), etc., or polysorbate or poloxamer. Given the broad definition of the terms buffer, saccharide, and nonionic surfactant, the genus of formulations variations is vast. The liquid formulation has specific required functions, namely, the formulation must maintain the stability of the peptide conjugate. However, the specification fails to disclose the specific formulation components that have the required functions. The specification fails to adequately describe the specific components that would yield a formulation having the claimed stability. Thus, the genus of formulations has no correlation between their structure and function.
Furthermore, the specification does not disclose a representative number of species to describe the genus. Although the specification clearly sets forth a correlation between the specifically defined formulations in the examples and the function of providing stability to the claimed peptide conjugate, this correlation does not appear to be clearly present in the breadth of the claims. The claims set forth a broad genus of formulations and specify no particular buffer, saccharide, or nonionic surfactant. Given the breadth of the components coupled with the pH range of 4.5-7.5, the claims encompass formulations that can differ substantially from the few species disclosed. However, these species are not representative of the genus because there is no indication in the specification that other species encompassed by the genus that differ from these species disclosed will have the same functional characteristics and one of skill in the art would not be able to predict the operability of any species other than the one disclosed. When there is substantial variation within the genus, the specification must describe a sufficient variety of species to reflect the variation within the genus. Thus, the specification does not adequately reflect the structural diversity of the claimed genus, either by the establishment of "a reasonable structure-function correlation or through the disclosure of sufficient number of species that are "representative of the full variety or scope of the genus”. Therefore, the specification provides insufficient written description to support the genus of compositions encompassed by the claim. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that
"applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
As taught by Chang et al., proteins typically have a wide range of stability issues as a result of their complexity and delicate structural stability (See page 1, first paragraph) (Chang, B.S. and Hershenson, S. 2002. Practical approaches to protein formulation development in "Rationale Design of stable protein formulations-theory and practice" (J.F. Carpenter and M.C. Manning eds.) Kluwer Academic/Plenum publishers, New York. pp. 1-25.) Chang et al. also describe various conditions that accelerate protein degradation, which affect specific peptides differently depending on the physical and biological properties of the peptides (See page 5, tables 3 and 4). Chang et al. also state that because proteins are complex molecules composed of numerous reactive chemical groups and delicate three-dimensional structures, identifying a set of conditions to keep all components stable is virtually impossible. See page 1, paragraph 1. With regards to liquid formulations, Chang et al. teach that developing conditions to keep proteins stable in a liquid form for a pharmaceutically relevant storage time (e.g., two years) is not a simple task (See page 10).
For the instant formulation to maintain its stability, the composition components must overcome the challenges posed by the array of physical and biological properties associated with protein formulations. As taught by Lassner et al., a basic principle of pharmaceutical protein formulations is that certain instabilities must be overcome (See Lassner et al., US2009/0226530, paragraph [0002). The specification does not provide substantive evidence that the claimed formulation would possess the claimed stability parameters, given the broad range of antibody and buffers, with consideration given to amino acid sequence, protein folding, domain localization and enzymatic or other activity. Without this demonstration, the skilled artisan would not be able to reasonably predict the outcome of the claimed formulation, i.e. would not be able to accurately predict if the claimed composition would result in an antibody formulation capable of the required functions for each claimed antibody species, which may have widely divergent physical and biological properties depending on the composition and/or amino acid sequence of the therapeutic protein. While the instant claims encompass a single antibody, the scope of the claims is vast, due to the broad genus of buffers recited.
Adequate written description requires more than a mere statement that is part of the invention. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chungai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
The University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines Inc. 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[The description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.").
Thus an Applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
MPEP § 2163.02 states, "[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed"1. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the Applicant must convey with reasonable clarity to those skilled in the art, that as of the filing date sought, he or she was in possession of the invention. The invention is for purposes of the "written description" inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601,1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications under the 35 USC §112 paragraph 1, "Revision 1" of Written Description Requirement (66 FR 1099-1111, March 25, 2008) state, "[possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention (Id. At 1104). Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was "ready for patenting" by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Double Patenting
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.
Claims 1-26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-14, and 16 of copending Application No. 17/627,913 in view of Carrier et al. (US Patent Application Publication 2009/0186819, published July 23, 2009.
The instant claims are drawn to a liquid formulation of a peptide conjugate, wherein the liquid formulation comprises: 18 nmol/mL to 940 nmol/mL of a peptide conjugate of Chemical Formula 1 below; a buffering agent in an amount for maintaining the pH of the liquid formulation in the range of 4.5 to 7.5; 1% (w/v) to 20% (w/v) of a saccharide; and 0.0010% (w/v) to 0.2% (w/v) of a nonionic surfactant: [Chemical Formula 1]
PNG
media_image1.png
270
684
media_image1.png
Greyscale
in Chemical Formula 1 above, Q is a peptide of General Formula 1 below; Z is an immunoglobulin Fc fragment; and n is a natural number, wherein the value of n is determined such that the average molecular weight of the [OCH2CH2]n region in the peptide conjugate is 10 kDa; [General Formula 1] His-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Xaa 12-Tyr-Leu-Asp-Xaa 16-Lys-Arg- Ala-Xaa20-Glu-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Cys (SEQ ID NO: 1), in General Formula 1 above, Xaa2 is 2-aminoisobutyric acid (Aib), Xaa12 is lysine (K), Xaa16 is glutamic acid (E), Xaa20 is lysine (K); and a lactam ring may or may not be formed between Xaa12 and Xaa16 or Xaa16 and Xaa20 residues.
The ‘913 claims teach a method of preparing a conjugate have the structure recited in the instant claims. The ‘913 teach that the conjugate comprises SEQ ID NO: 1, which is identical the SEQ ID NO: 1 of the instant claims. The ‘913 teach that the conjugate comprises a linker having the structure of formula 2 (See claim 11), which is identical to the linker of chemical formula I of the instant claims. The ‘913 claims teach that the conjugate comprises an immunoglobulin Fc region, wherein the immunoglobulin Fc region comprises the amino acid sequence of SEQ ID NO: 7 (See claims 13 and 14). It should be noted that SEQ ID NO: 7 is 100% identical to SEQ ID NO: 5 of the instant claims.
The ’913 claims do not teach the liquid formulation and excipients recited in the instant claims.
However, Carrier et al. teach a liquid formulation comprising an insulinotropic peptide conjugate, a buffer, a tonicity modifier, and a surfactant, wherein the formulation has a pH from about 4 to about 8 (See abstract and claim 1 and paragraph 0006-0008). Carrier et al. teach that the tonicity modifier is sucrose, which is a saccharide (See paragraph 0053). Carrier et al. teach that the surfactant is poloxamer 188 (See paragraph 0012).
It would have been obvious to one of ordinary skill in the art to formulate the peptide conjugate of the ‘913 claims according to the teachings of Carrier et al. to formulation a liquid formulation, as recited in the instant claims. One of ordinary skill in the art would be motivated to do so because would provide a stable pharmaceutical product that maintains its effectiveness. Regarding the concentration of the formulation components, the concentration of the components in the formulation are result effective variables that can be optimized by one of ordinary skill in the art. Therefore, one of ordinary skill in the art would be motivated to select the instantly claimed excipients and stabilizers and adjust their concentrations as needed to produce a stable liquid formulation comprising the peptide conjugate. One of ordinary skill in the art would be motivated to do so, in view of the art-recognized need to optimize formulations of therapeutic peptide conjugates, and have a reasonable expectation of success, based on the extensive knowledge and skill in the art in view of the routine nature of the experimentation involved.
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.).
This is a provisional nonstatutory double patenting rejection.
Claim Status
No claims are allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SANDRA CARTER whose telephone number is (571)272-2932. The examiner can normally be reached 8:00-5:00 pm.
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, Vanessa L. Ford can be reached at (571)272-0857. 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.
/SANDRA CARTER/Examiner, Art Unit 1674
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674