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 preliminary amendment filed 10 June 2025 has been received and entered. Claims 10-11, 13-14, 16-18 and 24 have been canceled. Claims 1-9, 12, 15 and 19-23 are currently pending.
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 10 June 2025 is acknowledged.
Applicant also elects a polypeptide comprising the amino acid sequence of SEQ ID NO:6 for the species of FGF21 mutant, a polypeptide comprising the amino acid sequence of SEQ ID NO:9 for the GLP-1 receptor agonist and diabetes mellitus for the disease/disorder.
Claims 15 (in part) and 19-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 5 and 23 are withdrawn from further considering pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 June 2025.
Applicant should note that the election of an FGF21 variant with the amino acid sequence of SEQ ID NO:6 does not read on ANY of the claims presented in the instant application. An alignment of SEQ ID NO:2 (native mature FGF21 (lacking a signal sequence)) and SEQ ID NO:6 is provided below:
PNG
media_image1.png
337
585
media_image1.png
Greyscale
SEQ ID NO:2 is the query line (Qy) and SEQ ID NO:6 is the database line (Db) and the elected species. SEQ ID NO:6 is mature FGF21 with cysteine substitutions at positions 27 and 121 and a deletion at position 171. However, none of these modifications relative to mature FGF21 corresponds to the mutations recited in claim 1 and SEQ ID NO:6 is not encompassed by claim 1 (or any of the other independent claims 9 and 15).
Claims 1-4, 6-9, 12, 15 and 21-22 will be examined with respect to the FGF21 compound as currently recited and art will be applied to the embodiment of SEQ ID NO:6 even though it does not read on the current claims. Applicant will need to either amend the claims to encompass the elected species or elect a different species of FGF21 compound that does read on the claims in the next response. Failure to do so may result in a non-compliant amendment/response.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The information disclosure statement (IDS) submitted on 26 June 2024 and 10 June 2025 have been considered by the examiner. With regard to items which have been lined through, the information contained therein has been considered but as the reference citations are incomplete, they are lined through (see 37 CFR 1.98(b)(5)).
Improper Markush
Claim 15 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Regarding claim 15, the Markush grouping of combination, pharmaceutical composition, fusion molecule, nucleic acid molecule, and host cell is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the various recited members of the Markush grouping do not belong to a recognized class and they do not share a common structure which provides for their common function.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Objections
Claim 6 is objected to because of the following informalities: the claim recites “comprises or consists of an amino acid sequence”. “An” is an indefinite article yet the claim refers to a singular sequence. The term “an” should be amended to recite “the”, which would be grammatically correct. 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 1-4, 6-9, 12, 15 and 21-22 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 claims are directed to a combination of FGF21 compound and a GLP-1R agonist “wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- to 531-fold reduced as compared to the GLP-1R agonistic activity of native GLP-1(7-36)”. Claims 2-3, 12, and 21 recite various other activity ranges which fall in between the 9- to 531-fold range. The claims do not recite any particular structure for the claimed GLP-1R agonist and only recite a functional characteristic of the molecules being claimed.
The specification discloses exendin derived peptides with the amino acid sequences of SEQ ID NO:25-26, 28, 30-33 and 35-36 with reduced GLP-1R agonistic activity which fall in between the 9- to 531-fold range (see Table 3 at page 42 of the specification). Claim 6 includes a formula for GLP-1R agonist molecules, however, this formula does not necessarily result in molecules which have the recited activity range (for example, SEQ ID NO:24, 27, 29 and 34). Claim 7 recites a number of molecules with the amino acid sequences of SEQ ID NO:9, 10, 12, 14, 15, 16, 17, 19 and 20, but there is no disclosure in the specification as to what activity level is possessed by proteins with these amino acid sequences. It is noted that the elected species of GLP-1R agonist has the amino acid sequence of SEQ ID NO:9
The structure of the claimed GLP-1R agonists with the specified activity levels are not adequately described. In AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., Ill USPQ2d 1780 (Fed. Cir. 2014) AbbVie had claims to functionally claimed antibodies and Centocor presented evidence that the antibodies described in AbbVie's patents were not representative of other members of the functionally claimed genus. The decision states, “When a patent claims a genus using functional language to define a desired result, ‘the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.’ Id. at 1349. We have held that 'a sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus.’ Id. at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). Here, the claimed invention is a class of fully human antibodies that are defined by their high affinity and neutralizing activity to human IL-12, a known antigen. AbbVie's expert conceded that the '128 and '485 patents do not disclose structural features common to the members of the claimed genus.”
The AbbVie decision considers how large of a genus is involved and what species of the genus are described in the patent. With the written description of a genus, however, merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus. See Ariad, 598 F.3d at 1353 (The written description requirement guards against claims that “merely recite a description of the problem to be solved while claiming all solutions to it and ... cover any compound later actually invented and determined to fall within the claim's functional boundaries.”).
In the instant application, the specification and claims draw a fence around a perceived genus but the genus is not adequately described. The specification exemplifies GLP-1R agonists which have the amino acid sequences of SEQ ID NO:25-26, 28, 30-33 and 35-36 with reduced GLP-1R agonistic activity which fall in between the 9- to 531-fold range as claimed; however, the claims are not limited to this and the structural variability of the claimed genus is large with regard to the functional recitation in claims 1-3, 9, 12, 15 and 21. No reasonable structure-function correlation has been established that is commensurate in scope with the claims. The specification does not describe representative examples to support the full scope of the claims as only SEQ ID NO:25-26, 28, 30-33 and 35-36 fall within the recited range and other embodiments which are encompassed by SEQ ID NO:37 (GLP-1R agonist formula in claim 6) do not fall within the recited range.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states 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, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). A review of the language of the claim indicates that these claims are drawn methods which require antibodies which have specific functional characteristics.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(1), the court states, “An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.”
Thus, given the level of skill and knowledge and predictability in the art, those of skill in the art would not conclude that the applicant was in possession of the claimed genera of proteins (GLP-1R agonists) which have reduced GLP-1R agonistic activity which fall in between the 9- to 531-fold range. "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004). For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly.
Further, it is not sufficient to define the genus solely by its principal biological property, because an alleged conception having no more specificity than that is simply a wish to know the identity of any material with that biological property. Per the Enzo court's example, (Enzo Biochem, Inc. v. Gen-Probe Inc., 63 USPQ2d 1609 (CA FC 2002) at 1616) of a description of an anti-inflammatory steroid, i.e., a steroid (a generic structural term) couched "in terms of its function of lessening inflammation of tissues" which, the court stated, "fails to distinguish any steroid from others having the same activity or function" and the expression "an antibiotic penicillin" fails to distinguish a particular penicillin molecule from others possessing the same activity and which therefore, fails to satisfy the written description requirement. Similarly, the function of the variant as claimed does not distinguish a particular variant from others having the same activity or function and as such, fails to satisfy the written-description requirement. Applicant has not disclosed any relevant, identifying characteristics, such as structure or other physical and/or chemical properties, sufficient to show possession of the claimed genus. Mere idea or function is insufficient for written description; isolation and characterization at a minimum are required. A description of what a material does, rather than what it is, usually does not suffice. (Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406).
In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus, which are GLP-1R agonists with reduced GLP-1R agonistic activity which fall in between the 9- to 531-fold range. One of skill in the art would not recognize from the disclosure that the applicant was in possession of the genus. 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).
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
With regard to claims 1 and 9, the claims recite an FGF21 compound with “a mutation of 1 to 10 amino acid residues for reducing immunogenicity of the FGF21 variant as compared to native FGF21 of SEQ ID NO:2”. The specification fails to provide an adequate written description of such mutations. There is no disclosure in the specification or the prior art of record as to which amino acids may be involved in immunogenicity or what mutations should be made and could be made such that the FGF21 protein retains functionality, as required by the claims. The claims are reciting a characteristic (reduced immunogenicity) without any corresponding structure to provide for such activity. For the reasons addressed above with regard to the GLP-1R agonist claims based on functionality alone, the claims with regard to the FGF21 compound and the envisioned mutations also lack written description as the specification fails to provide any necessary structure for achieving the desired outcome.
With regard to claims 1, 9 and 15, the claims recite that “the FGF21 compound has an FGF21 activity which is the same as the FGF21 activity of native FGF21”. However, the instant specification fails to support the functional recitation of the claims. It is noted that the specification does not appear to have made any of the FGF21 compounds with the recited mutations in claims 1, 9 and 15. As the PTO does not have the facilities to make and test the FGF21 mutants of the claims, comparison to the closest prior art may be useful. U.S. Pat. No. 11,136,364 (Kim et al.) teach FGF21 mutants which have mutations as recited in the instant claims (see 102 rejection below). While Kim et al. did not test the functionality of the FGF21 variants alone, Kim et al. did test the functionality of FGF21-Ig fusions and the activity of the fusions with the mutant FGF21s were compared to the activity of native FGF21 fused to an Ig molecule. From Figure 6, it is clear that the activity of the mutant FGF21-Ig molecules was not “the same” as native FGF21-Ig molecules. While this is not a direct comparison of the activity of the mutants with the native FGF21, it is clearly evidence that the mutant FGF21 molecules do not have the same activity as native FGF21. One of ordinary skill in the art would not reasonably conclude that mutation of FGF21 in the manner claimed would result in an FGF21 mutant with the same activity as native FGF21 because the molecules are structurally different and differences in activity would be expected, absent evidence to the contrary. Kim et al. teach at Table 1 what the expected effects of the mutations will be on the FGF21 molecule, including improvement of stability and pharmacokinetics. Such improvements would be expected to alter the functionality of the FGF21 protein. Therefore, the instant specification fails to provide an adequate written description for FGF21 compounds as recited in claims 1, 9 and 15 which have “and FGF21 activity which is the same as the FGF21 activity of native FGF21” absent evidence to the contrary.
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 1, 4, 9, 15 and 22 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 1, 9 and 15 are indefinite because the FGF21 variant is said to comprise at least one mutation selected from a group of mutations. In so far as the claim encompasses more than one of the recited substitutions, it is not clear how the various substitutions would be combined and what the final molecule would constitute. The second recited substitution is at positions 170-174 as is the third recited substitution. The third substitution is at position 170 and the fourth is at position 174. Because the positions overlap, it is not clear what the final molecule would be if all 4 substitutions were included in a single molecule. Furthermore, because the last recited mutation is one of 1-10 amino acid residues “for reducing immunogenicity of the FGF21 variant” and there are no positions recited, the metes and bounds of what might be encompassed considering the additional substitutions above which might include amino acid residues that impact immunogenicity are indefinite.
Claims 1, 9 and 15 recite “substantially the same” with regard to FGF21 activity. However, the term “substantially” in the claims is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification at page 16, lines 12-14 states that the term “substantially the same” refers to an FGF21 activity which is in the range of 50-150% or 60-140% or 65-135% of the FGF21 activity of native FGF21. The specification also states that the term “FGF21 activity” refers to activation of the FGF21 receptor in one embodiment but also activity/potency in vitro and activity/potency in vivo and autophosphorylation upon contact in vitro (see page 16, lines 16-24). Determination of activity can be performed in vitro by measuring FGF21 receptor autophosphorylation or in vivo using an In-Cell Western (ICW) assay. The claim is indefinite because it is not clear if one measure of activity meets the definition in the specification but another measure of activity does not meet the definition if the limitation of “substantially” would be met or not. Therefore, the metes and bounds of the term “substantially” are not clearly set forth such that one of ordinary skill in the art would know if the limitation is or is not met by any particular FGF21 compound.
Claims 4 and 22 are indefinite for the recitation of “to an amino acid sequence of the native FGF21”. First, there is a lack of antecedent basis for “the native FGF21”. As there are multiple native FGF21 proteins (from different species which may differ in amino acid sequence) and claims 1 and 9 refer to “a native FGF21” in the first wherein clause, therefore “the native FGF21” lacks antecedent basis. Secondly, the recitation of “to an amino acid sequence of the native FGF21” is indefinite as “an” is an indefinite article and it is not clear which amino acid sequence of FGF21 is intended. Therefore, the metes and bounds of the claims cannot be determined.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 4 and 22 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 4 and 22 recite that the FGF21 variant has at least 80% or at least 90% or at least 95% amino acid sequence identity to the amino acid sequence of native FGF21. However, this limitation broadens the scope of the subject matter of claims 1 and 9. If all of the mutations recited in claims 1 and 9 were applied to FGF21, that would equate to 21 point mutations, and the resultant protein would have 88% identity to FGF21. Therefore, claims 4 and 22 would attempt to broaden the subject matter of claim 1 by encompassing more variation than claim 1 provides. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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)(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.
Claim(s) 1-4, 6, 9, 12, 15 and 21-22 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by U.S. Pat. No. 11,136,364 (Kim et al.).
Kim et al. teach a dual function protein which comprises an FGF21 mutant protein and a biologically active protein wherein the FGF21 mutant protein has improved pharmacokinetic parameters, high stability, low possibility of forming aggregation complexes and reduced potential immunogenicity (see col. 4, lines 25-30). Kim et al. teach that the FGF21 mutant protein comprises at least one mutation selected from the group consisting of the following mutations (1) to (7):
PNG
media_image2.png
385
409
media_image2.png
Greyscale
The FGF21 mutant protein of Kim et al. is the same as what is found in the instant claims 1, 9 and 15. Kim et al. teach that the FGF21 mutant protein is part of a dual function protein which also comprises a biologically active protein which may be one of a number of proteins (see column 8, beginning at line 58). Kim et al. preferably teach that the biologically active protein may be selected from GLP-1, a mutant thereof and exendin-4.
The amino acid sequence for Extendin-4 is: HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS. Extendin-4 comprises the amino acid sequence of SEQ ID NO:37 of the instant application when X10 is L, X12 is K, X14 is M, X15 is E, X18 is A, X20 is R, X21 is L, X27 is K and X28 is N. See also claim 4 of Kim et al.
Kim et al. also teaches a dual function protein that additionally comprises an Fc region (see column 9, beginning at line 13). The Fc region is said to encompass an entire Fc region, a fragment thereof, or an Fc region mutant and may be a hybrid Fc (see line 39). The construct is described at line 66, column 9 to line 29, column 10. With regard to claim 6 which comprises additional amino acid residues at the N- and C-terminus of “the amino acid sequence”, Kim et al. disclose linkers which may be present on the N- or C-terminus of the FGF-21 mutant and depending on the orientation of the fusion protein, these linkers would also end up on the N- or C-terminus of the GLP-1 mutant, thereby meeting the limitations of claim 6.
Kim et al. additionally teach pharmaceutical compositions which comprise the FGF21 and GLP-1R combination of the instant claims and teach that the composition may be administered and that a carrier or vehicle “may be added to the composition and be delivered to a patient” (see column 12, lines 8-26). While Kim et al. does not explicitly recite a “kit” (instant claim 15), the disclosure of a kit in clearly provided as the composition in addition to a carrier or vehicle is described in Kim et al. and such would be construed as a “kit” as it has all the components recited in the instant claim.
Kim et al. do not specifically state the agonistic activity of the GLP-1 mutant (extendin-4) in relation to native GLP-1. However, claim 1 of the instant application requires the GLP-1R agonist to have an activity which is 9 to 531-fold reduced compared to native GLP-1. Claim 6 of the instant application which recites the formula of SEQ ID NO:37 (and which encompasses exendin-4) depends from claim 1, therefore, exendin-4 would necessarily have an activity which is 9 to 531-fold reduced compared to native GLP-1, absent evidence to the contrary. Therefore, Kim et al. anticipate the instant claims.
Claim(s) s 1-4, 6-9, 12, 15 and 21-22 is/are rejected under 35 U.S.C. 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over U.S. Pat. No. 10,583,174 (Göbel et al.).
The applied reference (U.S. Pat. No. 10,583,174) has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
NOTE: The instant rejection is based on the election of an FGF21 variant having the amino acid sequence of SEQ ID NO:6. As pointed out previously, this election is not encompassed by the limitations of the instant claims (as the substitutions recited in claims 1, 9 and 15 are not found in the FGF21 variant having the amino acid sequence of SEQ ID NO:6). However, as the subject matter of a combination comprising an FGF21 compound and a glucagon-like peptide-1 receptor (GLP-1R) agonist wherein the FGF21 compound has the amino acid sequence of SEQ ID NO:6 and the GLP-1R agonist has the amino acid sequence of SEQ ID NO:9 is fully disclosed in ‘174, the rejection is being put on the record.
U.S. Pat. No. 10,583,174 (Göbel et al.) teaches a combination of FGF21 compound with a GLP-1R agonist wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21 and wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- 531-fold reduced compared to the GLP-1R agonistic activity of native GLP-(7-36) and wherein the GLP-1R agonist comprises or consists of the amino acid sequence of SEQ ID NO:37 with “X” amino acids as recited in claim 1 of ‘174. Göbel et al. additionally claim the same activity ranges for the GLP-1R agonist as in instant claims 2-3 and 12 (see claims 2-3 of ‘174). Göbel et al. also claim the GLP-1R agonist by amino acid sequence (claim 5) which corresponds to the instant claim 7, as well as N-terminal and C-terminal additional amino (instant claim 6 and claims 6-8 of ‘174). Göbel et al. teaches a kit which includes one or more containers (see column 23, lines 8-26).
Göbel et al. teaches that “the GLP-1R agonist having a GLP-1R agonist activity which is reduced as compared to that of native GLP-1(7-36) as defined herein comprises or consists of an amion acid sequence selected from the group consisting of SEQ ID Nos: 9, 10, 12, 14, 15, 16, 17, 19 and 20” (see column 15, lines 19-24).
Göbel et al. teaches that “the FGF21 compound is an FGF21 variant comprising or consisting of an amino acid sequence selected from the group consisting of SEQ ID Nos: 3, 4, 5 and 6” (see column 11, lines 48-51).
Therefore, Göbel et al. clearly teaches a combination comprising an FGF21 compound having the amino acid sequence of SEQ ID NO:6 (the elected species) and a GLP-1R agonist having the amino acid sequence of SEQ ID NO:9 (the elected species) wherein the GLP-1R agonistic activity is the same as recited in the instant claims as pointed out above. Göbel et al. additionally teaches pharmaceutical compositions and kits as described above and therefore, Göbel et al. anticipates the instant claims (as they are directed to the elected species of FGF21 and GLP-1R).
In the even that Göbel et al. does not anticipate the instant claims with respect to an FGF21 compound having the amino acid sequence of SEQ ID NO:6 (the elected species) and a GLP-1R agonist having the amino acid sequence of SEQ ID NO:9 (the elected species), Göbel et al. makes obvious the combination because the two recited species are clearly disclosed in Göbel et al. and it is taught that the FGF21 compound and the GLP-1R compound can be any of those which are disclosed in Göbel et al. as well as selected from compounds known in the art. One would be motivated to select the specific FGF21 compound and GLP-1R compound (SEQ ID NO:6 and 9, respectively) because they were 2 of the specifically defined and recited compounds in the disclosure of Göbel et al.
Claim Rejections - 35 USC § 103
Claims 1-4, 6-9, 12, 15 and 21-22 is/are rejected under 35 U.S.C. 103 as being obvious over U.S. Pat. No. 10,583,174 (Göbel et al.) in view of U.S. Pat. No. 11,136,364 (Kim et al.).
The applied reference (U.S. Pat. No. 10,583,174) has a common applicant with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
U.S. Pat. No. 10,583,174 (Göbel et al.) teaches a combination of FGF21 compound with a GLP-1R agonist wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21 and wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- 531-fold reduced compared to the GLP-1R agonistic activity of native GLP-(7-36) and wherein the GLP-1R agonist comprises or consists of the amino acid sequence of SEQ ID NO:37 with “X” amino acids as recited in claim 1 of ‘174. Göbel et al. additionally claim the same activity ranges for the GLP-1R agonist as in instant claims 2-3 and 12 (see claims 2-3 of ‘174). Göbel et al. also claim the GLP-1R agonist by amino acid sequence (claim 5) which corresponds to the instant claim 7, as well as N-terminal and C-terminal additional amino (instant claim 6 and claims 6-8 of ‘174). Göbel et al. teaches a kit which includes one or more containers (see column 23, lines 8-26). Göbel et al. does not teach an FGF21 compound which is an FGF21 variant comprising at least one mutation selected from the group consisting of:
PNG
media_image2.png
385
409
media_image2.png
Greyscale
Kim et al. teach a dual function protein which comprises an FGF21 mutant protein and a biologically active protein wherein the FGF21 mutant protein has improved pharmacokinetic parameters, high stability, low possibility of forming aggregation complexes and reduced potential immunogenicity (see col. 4, lines 25-30). Kim et al. teach that the FGF21 mutant protein comprises at least one mutation selected from the group consisting of the following mutations (1) to (7):
PNG
media_image2.png
385
409
media_image2.png
Greyscale
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to have substituted the FGF21 variants of Kim et al. for the FGF21 compound of Göbel et al. to generate the combination of Göbel et al. with the improved pharmacokinetic parameters, high stability, low possibility of forming aggregation complexes and reduced potential immunogenicity which is gained by the FGF21 mutants of Kim et al. One of ordinary skill in the art would have a reasonable expectation of success because Kim et al. used the same FGF21 variants in a dual fusion protein with a GLP-1 variant for the same purpose as Göbel et al. Therefore, the invention as a whole would have been obvious, absent evidence to the contrary.
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
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 1-4, 6-9, 12, 15 and 21-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 and 12-15 of U.S. Patent No. 10,583,174 (Göbel et al.) in view of U.S. Pat. No. 11,136,364 (Kim et al.).
U.S. Pat. No. 10,583,174 (Göbel et al.) teaches a combination of FGF21 compound with a GLP-1R agonist wherein the FGF21 compound has an FGF21 activity which is the same or substantially the same as the FGF21 activity of native FGF21 and wherein the GLP-1R agonist has a GLP-1R agonistic activity which is 9- 531-fold reduced compared to the GLP-1R agonistic activity of native GLP-(7-36) and wherein the GLP-1R agonist comprises or consists of the amino acid sequence of SEQ ID NO:37 with “X” amino acids as recited in claim 1 of ‘174. Göbel et al. additionally claim the same activity ranges as in claims 2-3 and 12 (see claims 2-3 of ‘174). Göbel et al. also claim the GLP-1R agonist by amino acid sequence (claim 5) which corresponds to the instant claim 7, as well as N-terminal and C-terminal additional amino acids (claim 6). Göbel et al. does not teach an FGF21 compound which is an FGF21 variant comprising at least one mutation selected from the group consisting of:
PNG
media_image2.png
385
409
media_image2.png
Greyscale
Göbel et al. does not claim a kit.
Kim et al. teach a dual function protein which comprises an FGF21 mutant protein and a biologically active protein wherein the FGF21 mutant protein has improved pharmacokinetic parameters, high stability, low possibility of forming aggregation complexes and reduced potential immunogenicity (see col. 4, lines 25-30). Kim et al. teach that the FGF21 mutant protein comprises at least one mutation selected from the group consisting of the same mutations (1) to (7) as presented above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to have substituted the FGF21 variants of Kim et al. for the FGF21 compound of Göbel et al. to generate the combination of Göbel et al. with the improved pharmacokinetic parameters, high stability, low possibility of forming aggregation complexes and reduced potential immunogenicity which is gained by the FGF21 mutants of Kim et al. One of ordinary skill in the art would have a reasonable expectation of success because Kim et al. used the same FGF21 variants in a dual fusion protein with a GLP-1 variant for the same purpose as Göbel et al.
Kim et al. additionally teach pharmaceutical compositions which comprise the FGF21 and GLP-1R combination of the instant claims and teach that the composition may be administered and that a carrier or vehicle “may be added to the composition and be delivered to a patient” (see column 12, lines 8-26). It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to include the FGF21 and GLP-1R combination of Göbel et al. made obvious by Kim et al. in a container because Kim et al. teach that the combination is useful as a pharmaceutical and pharmaceuticals are routinely placed in containers. Additionally, because Kim et al. indicate that carriers or vehicles may be added to the composition, this would require a container to which the carrier/vehicle would be added so that the combination could be mixed with the carrier/vehicle. Lastly, Kim et al. teach administration routes which would require injection or infusion which would necessarily require a container (i.e. a syringe or IV bag). Therefore, the invention was a whole would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application, absent evidence to the contrary.
Citation of Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US Pat. No. 11,230,582 : discloses FGF21 variants with increased stability and increased potency/efficacy. ‘582 specifically discloses an FGF21 variant which has the same amino acid sequence as that of instant SEQ ID NO:6 as well as fusions with GLP-1 receptor agonists (see claim 4). See alignment of FGF21 variant below.
Alignment of SEQ ID NO:6 with SEQ ID NO:46 of U. S. Pat. No. 11,230,582
RESULT 1
AASEQ2_10082025_124743
Query Match 100.0%; Score 969; DB 1; Length 181;
Best Local Similarity 100.0%;
Matches 180; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 HPIPDSSPLLQFGGQVRQRYLYTDDACQTEAHLEIREDGTVGGAADQSPESLLQLKALKP 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 2 HPIPDSSPLLQFGGQVRQRYLYTDDACQTEAHLEIREDGTVGGAADQSPESLLQLKALKP 61
Qy 61 GVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHGLPLHLPG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 62 GVIQILGVKTSRFLCQRPDGALYGSLHFDPEACSFRELLLEDGYNVYQSEAHGLPLHLPG 121
Qy 121 CKSPHRDPAPRGPARFLPLPGLPPAPPEPPGILAPQPPDVGSSDPLSMVGSQGRSPSYAS 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 122 CKSPHRDPAPRGPARFLPLPGLPPAPPEPPGILAPQPPDVGSSDPLSMVGSQGRSPSYAS 181
US PGPUB 2023/0265482: discloses fusions of GLP-1R agonists and FGF21 variant polypeptides, including FGF21 variant which corresponds to SEQ ID NO:6 of the instant application.
Conclusion
No claim is allowed.
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, 6am-2:30pm.
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, Gary Nickol can be reached on 571-272-0835. 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.
/Christine J Saoud/Primary Examiner, Art Unit 1645