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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission of RCE on 3/4/26 and the amendment of claims has been entered.
Election/Restrictions
Applicant’s election without traverse of GLP-2 (protein active agent), 5:3:2 (V:G:A ratio), SEQ ID NO: 3 and human subject was previously acknowledged.
In the reply filed 3/3/26, Applicants amended claims 1 and 20. Claim 19 was cancelled.
Claims 1-3, 5, 13-14 and 20 are pending.
Claims 1-3, 5, 13-14 and 20 are under consideration.
Claim Rejections -Withdrawn
The rejection of claims 1-3, 5, 13-14 and 19-20 under 35 U.S.C. 103 as being unpatentable over Chilkoti et al. (US 2010/0022455, cited on IDS) in view of Alters et al. (“GLP2-2G-XTEN: a Pharmaceutical protein with improved serum half-life and efficacy in a Rat Crohn’s disease model” PLoS One, 2012; 7(11): e50630, cited on IDS (reference 381)) is withdrawn due to amendment of the claims.
Claim Objections-Withdrawn
The objection to claim 1 is withdrawn due to amendment of the claim.
Claim Rejections - 35 USC § 103-NEW
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.
Claims 1-3, 5, 13-14 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Chilkoti et al. (US 2010/0022455, cited on IDS) in view of Alters et al. (“GLP2-2G-XTEN: a Pharmaceutical protein with improved serum half-life and efficacy in a Rat Crohn’s disease model” PLoS One, 2012; 7(11): e50630, cited on IDS (reference 381)) and Isaacs (WO2001049314).
Chilkoti et al. teach therapeutic agents and compositions comprising elastin-like peptides and therapeutic proteins (Abstract). Chilkoti et al. teach the ELP component provides therapeutic advantages to the therapeutic agent, such as better stability, solubility, bioavailability, bioavailability, half-life, persistence, and/or biological action of the therapeutic agent [0007].
With respect to “a sustained release pharmaceutical formulation”, Chilkoti et al. teach the ELP component provides alternative advantages such as in vivo formation of a drug depot for sustained release of the therapeutic agent [0071].
With respect to the limitation “… therapeutic agent comprising a protein active agent and ELP structural units selected from SEQ ID NO: 3, Chilkoti et al. teach the ELP component is SEQ ID NO: 3 wherein X is V, G and A at a ratio of 5:3:2 (Fig. 1). Please note that SEQ ID NO: 3 from Chilkoti et al. meets the limitations of instantly claimed SEQ ID NO: 3. Chilkoti et al. teach construction of ELP V5A2G3 with 10, 20, 60, 90 and 180 structural units [0178]. Chilkoti et al. teach the sequence of a conjugate of a therapeutic agent and ELP120 (SEQ ID NO: 56), which comprises 120 ELP repeats. The ELP portion is identical to the ELP portion of instantly claimed SEQ ID NO: 71.
With respect to the limitation “for systemic administration”, Chilkoti et al. provides examples of ELP fusion proteins administered intravenously and subcutaneously [0026-0027], meeting the limitation of “systemic administration”.
With respect to the “protein active agent is GLP-2 receptor agonist..+”, Chilkoti et al. does not teach an example of a fusion protein of a GLP-2 receptor agonist (elected species) and the ELP structural units, however the reference is suggestive of the fusion protein. The teachings of Alters et al. also cure this deficiency.
Chilkoti et al. teach in addition to GLP-1, other peptides of this family, such as those derived from processing of the proglucagon gene, such as GLP-2 could be conjugated or fused to the ELP component to enhance the therapeutic potential [0105]. Please note that the instant specification discloses that the GLP-2 receptor agonist can be a GLP-2 peptide [0111].
Chilkoti et al. does not teach the fusion protein is SEQ ID NO: 71. However, the teachings of Alters et al. cure this deficiency.
Alters et al. teaches that GLP-2 has a short half-life in human circulation of about 7 minutes due to rapid proteolytic degradation as well as removal from circulation by kidney filtration (p. 2, 1st col., 3rd para.). Alters et al. teach the sequence of GLP-2 receptor agonist that meets the limitation of GLP-2 receptor agonist portion of instantly claimed SEQ ID NO: 71 (p.2, 1st col. Materials and Methods para.).
It would have been obvious to a person of ordinary skill in the art to create a fusion protein of GLP-2 peptide and ELP in order to improve the properties of the peptide, such as bioavailability, solubility, half-life and increased stability as taught by Chilkoti et al. A person of ordinary skill in the art would be motivated to increase the stability and half-life of GLP-2 because it has a short half-life due to rapid proteolytic degradation as taught by Alters et al. Therefore, a person of ordinary skill would look to the teachings of Chilkoti et al. and Alters et al. and be justified in creating a fusion protein of GLP-2 and ELP structural units in order to improve the properties of the peptide. Importantly, a fusion protein comprising GLP-2 receptor agonist of Alters et al. and the ELP120 of Chilkoti et al. would be identical to instantly claimed SEQ ID NO: 71. There is a reasonable expectation of success given that Chilkoti et al. teach the ELP fusion proteins have increased half-life (see Fig. 14 and 15). Moreover, the GLP-2 agonist sequences are well known in the art.
The references do not teach the new limitation “wherein the therapeutic agent is present in the range of about 1 mg/ml to about 200 mg/ml”. However, the teachings of Isaacs cure this deficiency.
Isaacs teaches and claims formulation of GLP-2 at concentrations from about 0.1 to about 50 mg/ml. Isaacs teaches that that the medically useful amount of GLP-2 is from about 0.1 to 50mg/ml (p. 2, bottom para.).
With respect to claims 1 and 20, The concentration of the active agent in a composition is a result-effective variable and the determination of the optimum or workable ranges of said variable maybe characterized by routine experimentation (Please see MPEP 2144 II-Optimization of Ranges). In the instant case, Isaacs teaches the medically useful amount of GLP-2 is from about 0.1 to 50mg/ml. It would have been obvious and routine experimentation to a person of ordinary skill in the art with a reasonable expectation of success to optimize the concentration to arrive at the range of claim 1.
With respect to limitation “wherein the GLP-2 receptor agonist and the ELP form a reversible matrix at the body temperature of a subject, wherein the sustained release pharmaceutical PK profile has a reduced peak to trough ration (Cmax to Cmin) and longer to Tmax as compared to the PK profile for the GLP-2 receptor agonist in the absence of ELP” (claim 1), “..provides slow absorption from an injection site upon administration as compared to the absorption for the GLP-2 receptor agonist in the absence of the ELP” (claim 2), “provides a flat PK profile upon administration…” (claim 3) and “…wherein a reversible matrix formed at body temperature reverses…” (claim 5) the fusion protein made obvious by Chilkoti et al. and Alters et al. would inherently have all of the activities and properties of claims 1-3 and 5. 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)).” In other words, the combined references make obvious a fusion protein that meets the structural limitation of the instant claim 1 at the same concentration, therefore the same fusion proteins would have the same properties. Moreover, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
With respect to claims 13-14, Chilkoti et al. teach the invention provides a method for treating or preventing a disease in a human patient [0011]. Chilkoti et al. teach examples of the ELP fusion proteins administered to rats, meeting the limitation of “non-human mammal”.
Response to Arguments
Applicant's arguments filed 3/3/26 have been fully considered but they are not persuasive. Applicants argue that in order to form a matrix at the administrative temperature, the protein concentration of the therapeutic agent in the formulation can be adjusted and the protein concentration required for this purpose is determined by the type of ELP. In particular the concentration is disclosed as about 1 to 200 mg/ml, whereas for ELP4-120, the concentration is disclosed as about 0.005 to 10 mg/ml demonstrating that the protein concentration required for matrix formation differs significantly depending on the type of ELP. Applicants argue that neither reference discloses this feature. Applicants argue that while Chilkoti discloses ELP sequences, it makes no disclosure relevant to reversible matrix formation at body temperature and not disclosure of the protein concentration required for such matrix formation. Alters does not even disclose ELP sequences and therefore cannot disclose the protein concentration require. Applicants argue that the formulation as amended is not limited to the fusion protein itself but further requires that it is present at a specific concentration. In particular, the concentration enables the fusion protein to form a reversible matrix and body temp allowing slow absorption from the injection site into the bloodstream.
The arguments were considered but are not persuasive because one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, Chilkoti et al. teach in addition to GLP-1, other peptides of this family, such as those derived from processing of the proglucagon gene, such as GLP-2 could be conjugated or fused to the ELP component to enhance the therapeutic potential [0105]. Please note that the instant specification discloses that the GLP-2 receptor agonist can be a GLP-2 peptide [0104]. Alters et al. teaches that GLP-2 has a short half-life in human circulation of about 7 minutes due to rapid proteolytic degradation as well as removal from circulation by kidney filtration (p. 2, 1st col., 3rd para.). Therefore, the prior art is suggestive of creating a fusion protein of GLP-2 and ELP. Since the specific combination of GLP-2 and ELP is made obvious by the prior art, the same fusion protein would have identical properties. With respect to the concentration of the therapeutic agent, the concentration of the active agent is well known in the art. As taught by Isaacs, it would have been obvious to optimize the concentration to arrive at the amended claims since Isaacs teaches that the medically useful dose is within the claimed range. MPEP 2112 states: “There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.” In the instant case, the prior art makes obvious the identical structure claimed. Therefore, the same structure would necessarily have the same properties.
For the reasons presented above, the rejection is maintained.
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 1-3, 5, 13-14 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. USPN 10,722,590 in view of Alters et al. (“GLP2-2G-XTEN: a Pharmaceutical protein with improved serum half-life and efficacy in a Rat Crohn’s disease model” PLoS One, 2012; 7(11): e50630, cited on IDS (reference 381)).
Although the claims at issue are not identical, they are not patentably distinct from each other. The USPN claims a sustained release formulation comprising an active agent and a therapeutic agent comprising ELP (SEQ ID NO: 3). SEQ ID NO: 3 from USPN is identical to instantly claimed SEQ ID NO: 3. The USPN does not claim active agent is GLP-2, however the USPN teaches “In addition to GLP-1, other peptides of this family, such as those derived from processing of the pro-glucagon gene, such as GLP-2, GIP, and oxyntomodulin, can be conjugated or fused to the ELP component (as described herein) to enhance the therapeutic potential”. The MPEP 804 states” Further, those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application (as distinguished from an obvious variation of the subject matter disclosed in the reference patent or application). “.
The USPN does not teach the fusion protein is SEQ ID NO: 71. However, the teachings of Alters et al. cure this deficiency.
Alters et al. teaches that GLP-2 has a short half-life in human circulation of about 7 minutes due to rapid proteolytic degradation as well as removal from circulation by kidney filtration (p. 2, 1st col., 3rd para.). Alters et al. teach the sequence of GLP-2 receptor agonist that meets the limitation of GLP-2 receptor agonist portion of instantly claimed SEQ ID NO: 71 (p.2, 1st col. Materials and Methods para.).
It would have been obvious to a person of ordinary skill in the art to create a fusion protein of GLP-2 peptide and ELP in order to improve the properties of the peptide, such as bioavailability, solubility, half-life and increased stability as taught by the USPN. A person of ordinary skill in the art would be motivated to increase the stability and half-life of GLP-2 because it has a short half-life due to rapid proteolytic degradation as taught by Alters et al. Therefore, a person of ordinary skill would look to the teachings of USPN and Alters et al. and be justified in creating a fusion protein of GLP-2 and ELP structural units in order to improve the properties of the peptide. Importantly, a fusion protein comprising GLP-2 receptor agonist of Alters et al. and the ELP120 of Chilkoti et al. would be identical to instantly claimed SEQ ID NO: 71.
The USPN claims a concentration of 0.5 to about 200 mg/ml.
With respect to limitation “wherein the GLP-2 receptor agonist and the ELP form a reversible matrix at the body temperature of a subject, wherein the sustained release pharmaceutical PK profile has a reduced peak to trough ration (Cmax to Cmin) and longer to Tmax as compared to the PK profile for the GLP-2 receptor agonist in the absence of ELP” (claim 1), “..provides slow absorption from an injection site upon administration as compared to the absorption for the GLP-2 receptor agonist in the absence of the ELP” (claim 2), “provides a flat PK profile upon administration…” (claim 3) and “…wherein a reversible matrix formed at body temperature reverses…” (claim 5) the fusion protein made obvious by Chilkoti et al. and Alters et al. would inherently have all of the activities and properties of claims 1-3 and 5. 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)).” In other words, the combined references make obvious a fusion protein that meets the structural limitation of the instant claim 1 at the same concentration, therefore the same fusion proteins would have the same properties. Moreover, MPEP 2112.01 states: “Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.
Conclusion
No claims are allowed.
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/TARA L MARTINEZ/Examiner, Art Unit 1654
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