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 .
Response to Amendment
Applicant's response filed 10 December 2025 has been received and entered. Claims 17 and 18 have been amended. Claims 1-20 are currently pending. Claims 1-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 25 March 2025.
The text of those sections of Title 35, U.S. Code not included in this action can
be found in a prior Office action.
Any objection or rejection of record which is not expressly repeated in this action
has been overcome by Applicant's response and withdrawn.
Applicant's arguments filed 10 December 2025 have been fully considered but are not found to be persuasive.
Claim Objections
Claims 1-16 are currently pending but withdrawn as being directed to non-elected inventions. Claims 1-16 would not be subject to rejoinder and therefore, it is suggested that these claims be canceled.
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.
Claim 17 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing blood glucose level in a subject; reducing body weight in a subject; reducing triglyceride or low-density lipoprotein levels in a subject; and improving insulin sensitivity in a subject, does not reasonably provide enablement for treating diabetes and obesity as currently claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The instant claim is directed to treating diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis by administering a fusion protein of FGF21 and an Fc region of an immunoglobulin. The instant specification teaches that administration of a fusion of FGF21 variant-Fc in ob/ob male mice lowered blood glucose in a dose-dependent manner and reduced body weight (highest dose resulting in 6% reduction in body weight). The results are found in Figures 6 and 7A-7B. However, the results do not appear to rise to the level of statistical significance nor was there a clear indication that treatment with the FGF21 variant-Fc provided a therapeutic effect which would be discernable from the control group (vehicle-PBS). If the administration of the FGF21 variant-Fc does not produce a statistically significant effect, one of ordinary skill in the art would not reasonably conclude that administration of the compound would provide a therapeutic benefit which would rise to the level of a treatment for the recited conditions.
Example 5-2 administered 2 FGF21 variant-Fc proteins in an HFD/STZ mouse model (high fat diet, diabetes induced model) which resulted in an approximately 4% reduction in body weight (Figures 10A and 10B). Example 6-2 of the specification utilized a diet-induced obesity model (high-fat diet). A single subcutaneous injection of 30 nmol/kg of DFD18 resulted in 18% reduction in body weight. While Examples 5-2 and 6-2 resulted weight loss in the obesity model mice, there is no evidence that such results could be achieved in other mammals, especially in humans. In order for a treatment to be considered therapeutic for treatment of obesity, the weight loss which is achieved should be 3-5% to produce clinically meaningful health benefits and therefore, would be considered by one of ordinary skill in the art to be therapeutic in nature (see Jensen et al., Circulation 129(25, supp.2): S102-S138, 2014; page S109, middle of page). However, the results which were achieved in Examples 5-2 and 6-2 are not predictive of administration of FGF21 variant-Fc proteins in humans.
Gaich et al. (Cell Metabolism 18: 333-340, 2013) administered an FGF21 analog (LY2405319) to obese human subjects with type 2 diabetes. The FGF21 analog was administered for 28 days at a dose of 3, 10 or 20 mg per day. The treatment resulted in significant improvements in dyslipidemia (see abstract and Table 2). Gaich et al. report that reductions in mean body weight relative to baseline were “significant” but that changes in weight when compared to placebo did not reach statistical significance (see page 334, column 2, last paragraph). Figure 3 shows that while the reductions in mean body weight achieved statistical significance (from baseline), the percent change in mean body weight was less than 2% and was not statistically significant compared to placebo. Therefore, Gaich et al. demonstrate that while FGF21 can exert significant weight loss effects in a mouse model of obesity, these effects are not realized when FGF21 is administered to humans. Gaich et al. does provide evidence that administration for the treatment of dyslipidemia would be predictive. Lastly, the results of Gaich et al. would not support use of FGF21 for treating diabetes and specifically type 2 diabetes as the effects of the FGF21 analog on glucose and insulin were not statistically significant (see page 337).
Next, the animal model which was used in the instant specification is not an appropriate model for type-I diabetes nor is it an art accepted model for any of the other recited conditions recited in the claims except for obesity. However, while ob/ob mice are used to study obesity, the results of such studies are rarely directly applicable to humans. Rodents must be induced to become obese (fed high fat diets or be bred to alter their genetics). Rodents have a higher percentage of brown fat compared to humans. Humans have a tendency to eat for pleasure and therefore, a signal of satiety may result in a rodent ceasing to eat, it may not have the same effect in a human. With regard to a method of treating diabetes, while the ob/ob mouse model is used in studying type-2 diabetes, it would not be predictive of treating type-I diabetes as the physiological regulation of insulin and insulin sensitivity are not the same.
Lastly, the prior art suggests that it would be unpredictable to administer an FGF21 variant-Fc fusion for the treatment of obesity because obese subjects are FGF21 resistant. Fisher et al. (Diabetes 59: 2781-2789, 2010) teach that FGF21 levels are elevated in mouse models of obesity and that FGF21 levels correlate positively with BMI in humans. Fisher et al. stated that the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity (see abstract). Fisher et al. demonstrate that diet-induced obese mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. Fischer et al. speculate that FGF21 resistance is not a major cause of obesity and the data suggest that FGF21 resistance begins to manifest early during weight gain. Fischer et al. stated that “FGF21 has little effect on weight and only causes weight loss at high pharmacologic doses” (see page 2788, column 1, first paragraph). Therefore, one of ordinary skill in the art before the effective filing date of the claimed invention would not reasonably conclude that the instant claims are enabled for treatment of obesity or diabetes for the reasons provided above.
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.
Claims 17 and 18 (and dependent claims 19-20) 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.
Claims 17 and 18 have been amended to recite methods which administer a fusion protein wherein the fusion protein has a number of mutations (elements (a)(1) and (a)(2) in combination with one of (b)-(d) and “wherein the amino acid residue N of the FGF21 mutant protein in (c) and (d) is glycosylated, and the FGF21 mutant protein is connected to the Fc region of the immunoglobulin via a linker”.
The claims are indefinite because it is not clear if the limitation regarding the connection of the Fc region via a linker is to be applied to all of the encompassed fusion proteins or just to those fusion proteins which have the glycosylated N residue (embodiments which include (c) or (d)). Because the claims lack punctuation which would make clear if the linker limitation is to be applied to all the embodiments or just the glycosylated embodiments, the metes and bounds of the claim are unclear. Claims 19 and 20 are also indefinite as they do not obviate the issue pointed out in claims 17 and 18.
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 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 22-24 of U.S. Patent No. 11,136,364. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘364 encompass the same methods of the instant claims and administer the same fusion protein as the instant claims although no one claim is identical to the instant claims. Claim 22 of ‘364 is directed to the same method as instant claim 18. Claim 22 administers a composition which comprises the fusion protein of claim 1 which has the same modifications as the fusion protein of the instant claims. While claim 1 does not recite that the FGF21 mutant protein is connected to the Fc region by a linker, this element is claimed in claim 7 and it would be obvious to administer the fusion protein of claim 7 which comprises a linker. ‘364 additionally teaches the same patient population as that of instant claims 19-20 in claims 23-24. While ‘364 does not claim a method of treating diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis by administration of the fusion protein, such methods would have been obvious over claim 22 as a method which reduces blood glucose levels, reduces body weight, reduces triglyceride or LDL levels, and improves insulin sensitivity would make treatment of conditions in which these effects would mitigate disease symptoms would have been obvious. Therefore, the instant claims are not patentably distinct from the claims of ‘364.
Claims 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-16 of U.S. Patent No. 11,142,557. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘557 encompass the same methods of the instant claims and administer the same fusion protein as the instant claims although no one claim is identical to the instant claims. Claim 14 of ‘557 is directed to the same method as instant claim 18. Claim 14 administers a composition which comprises the fusion protein of claim 1 which includes the same modifications as the fusion protein of the instant claims. Claim 1 of ‘557 recites that the FGF21 mutant protein comprises one mutation, claim 17 includes additional mutations and it would be obvious to administer the fusion protein of claim 17 in the method of claim 14. While claim 1 does not recite that the FGF21 mutant protein is connected to the Fc region by a linker, this element is claimed in claims 4-7 and it would be obvious to administer the fusion protein of any of these claims which comprises a linker. ‘557 additionally teaches the same patient population as that of instant claims 19-20 in claims 15-16. While ‘557 does not claim a method of treating diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis by administration of the fusion protein, such methods would have been obvious over claim 14 as a method which reduces blood glucose levels, reduces body weight, reduces triglyceride or LDL levels, and improves insulin sensitivity would make treatment of conditions in which these effects would mitigate disease symptoms would have been obvious. Therefore, the instant claims are not patentably distinct from the claims of ‘557.
Claims 17-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 11,179,440. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘440 are directed to a method of treating hepatitis, hepatic fibrosis or hepatic cirrhosis in a subject in need thereof which administer the same fusion protein as the instant claims although no one claim is identical to the instant claims. The conditions which are treated in claim 1 of ‘440 are encompassed by the conditions to be treated in claim 17 and include the processes listed in claim 18 as hepatitis, hepatic fibrosis and hepatic cirrhosis are all conditions included in the pathology of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Claim 1 of ‘440 recites that the FGF21 mutant protein comprises one mutation, claim 10 includes an additional mutation at position 180 and claim 11 includes two mutations. It would have been obvious to include the various mutations recited in the claims of ‘440 in the fusion protein which is administered in the method of claim 1 because ‘440 teaches the various combinations of the instant claims. While claim 1 does not recite that the FGF21 mutant protein is connected to the Fc region by a linker, this element is claimed in claim 8 and it would be obvious to administer the fusion protein of any of these claims which comprises a linker. While ‘440 does not specifically identify the patient populations of instant claims 19 and 20, it would be obvious to practice the method of ‘440 in subjects who are obese or have diabetes because obesity and diabetes are risk factors for liver disease such as NASH, and treating hepatitis/hepatic fibrosis and hepatic cirrhosis are therapies for NASH. Therefore, the instant claims are not patentably distinct from the claims of ‘440.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Christine J Saoud whose telephone number is (571)272-0891. The examiner can normally be reached M-F, 8am-4pm.
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/Christine J Saoud/Primary Examiner, Art Unit 1645