DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing June 2, 2023 is pending.
Claims 1-13 are pending and currently under consideration.
Claim 1 is an independent claim.
Priority
The instant application is a 371 of PCT/KR2021/009934 filed 07/29/2021 and claims foreign priority to KR10-2020-0167844 filed 12/03/2020.
A translated copy of KR10-2020-0167844 has not been filed. Therefore, it is not clear if the foreign priority document has adequate support for the instant claims.
Claim Objections
Claim 2 objected to because of the following informalities:
Claim 2 currently recites:
“The fusion protein of claim 1, wherein the anti-OSCAR antibody including heavy chain variable domains and light chain variable domains comprises at least one selected from the group consisting of: 1) an anti-OSCAR antibody or fragments thereof including a heavy chain variable domain including SEQ ID NO: 1 and a light chain variable domain including SEQ ID NO: 2; 2) an anti-OSCAR antibody or fragments thereof including a heavy chain variable domain including SEQ ID NO: 3 and a light chain variable domain including SEQ ID NO: 4; and 3) an anti-OSCAR antibody or fragments thereof including a heavy chain variable domain including SEQ ID NO: 5 and a light chain variable domain including SEQ ID NO: 6”
where it should recite:
“The fusion protein of claim 1, wherein the anti-OSCAR antibody comprises a heavy chain variable domain (VH) and light chain variable domain (VL), wherein the VH and VL comprise: 1) SEQ ID NOs: 1 and 2, respectively; 2) SEQ ID NOs: 3 and 4, respectively; or 3) SEQ ID NOs: 5 and 6, respectively”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2 and 6 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.
Claim 2 recites the limitation "the anti-OSCAR antibody including heavy chain variable domains and light chain variable domains" in lines 1 and 2. Claim 2 is dependent on claim 1 which recites “an anti-OSCAR antibody” but not an “anti-OSCAR antibody including heavy chain variable domains and light chain variable domains.” Therefore, there is no antecedent basis for the limitation "the anti-OSCAR antibody including heavy chain variable domains and light chain variable domains" in claim 2.
Amending claim 2 to delete the phrase ”including heavy chain variable domains and light chain variable domains” would obviate this rejection.
Claim 6 recites the limitation "wherein asparagine at position 297 of the immunoglobulin Fc region is substituted with alanine" in lines 1 and 2. Claim 6 is dependent on claim 5 which recites “an immunoglobulin Fc region.” However, not all immunoglobulin Fc regions comprise an N297 residue. The N297 residue is restricted to the IgG class of antibodies and is not found in IgA, IgM, IgD, and IgE antibodies. Therefore, there is insufficient antecedent basis for the limitation "wherein asparagine at position 297 of the immunoglobulin Fc region is substituted with alanine" in claim 6.
Amending claim 6 to recite “wherein the immunoglobulin Fc region is derived from IgG and comprises an N297A point mutation” would obviate this part of the rejection.
Written Description
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 1-6 and 8-13 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 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 instant claims are drawn to a fusion protein comprising a glucagon-like peptide-1 (GLP-1) receptor agonist (RA) and an anti-osteoclast-associated receptor (OSCAR) antibody; a pharmaceutical composition for preventing or treating arthritis; a food composition for preventing or treating arthritis; a health functional food composition for preventing or treating arthritis; and a method of preventing or treating arthritis.
The Applicant has disclosed a single fusion protein (PF1803; SEQ ID NO: 7) which includes a GLP-1 RA and an anti-OSCAR antibody (e.g. see [0066]). It is noted that SEQ ID NO: 7 has the formula: GLP-1-Fc-VH-VL, wherein the GLP-1 (amino acids 1-31) is a dipeptidyl peptidase-IV (DPP-IV)-protected GLP-1 analogue (V8-GLP-1) (e.g. see Glaesner et al. Diabetes Metab Res Rev 2010; 26: 287–296, figure caption for FIG. 1C), the VH is SEQ ID NO: 5, the VL is SEQID NO: 6, and the Fc is SEQ ID NO: 9 which comprises as N297A point mutation. See sequence alignment below.
Query Match 81.8%; Score 2279.5; DB 1; Length 434;
Best Local Similarity 94.6%;
Matches 434; Conservative 0; Mismatches 0; Indels 25; Gaps 2;
Qy 1 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGSAPAPGGGGSDKTHTCPPCPAPELLGGP 60
|||||||||||||||||||||||||||||||
Db 1 HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGG----------------------------- 60
Qy 61 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYAS 60
Qy 121 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 TYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM 120
Qy 181 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ 180
Qy 241 QGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSEVQLLESGGGLVQPGGSLRLS 300
||||||||||||||||||||||||||||| |||||||||||||||||||||
Db 181 QGNVFSCSVMHEALHNHYTQKSLSLSPGK----------EVQLLESGGGLVQPGGSLRLS 230
Qy 301 CAASGFTFSDYYWTWVRQAPGKGLEWVSGSPVFGAANYAQNFQGRFTISRDNSKNTLYLQ 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 231 CAASGFTFSDYYWTWVRQAPGKGLEWVSGSPVFGAANYAQNFQGRFTISRDNSKNTLYLQ 290
Qy 361 MNSLRAEDTAVYYCAKAGIPGHFDIWGQGTLVTVSSGGGGSGGGGSGGGGSQSVLTQPPS 420
||||||||||||||||||||||||||||||||||| ||||||||||
Db 291 MNSLRAEDTAVYYCAKAGIPGHFDIWGQGTLVTVS---------------SQSVLTQPPS 335
Qy 421 ASGTPGQRVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYGNSNRPSGVPNRFSGSKSG 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 336 ASGTPGQRVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYGNSNRPSGVPNRFSGSKSG 395
Qy 481 TSASLAISGLRSEDEADYYCQSYDSSSWLFGGGTKLTVL 519
|||||||||||||||||||||||||||||||||||||||
Db 396 TSASLAISGLRSEDEADYYCQSYDSSSWLFGGGTKLTVL 434
The Applicant also discloses three sets of VH and VL pairs for the anti-OSCAR antibody including SEQ ID NOs: 1 and 2, 3 and 4, and 5 and 6, respectively, which can be used in the anti-OSCAR antibody-portion of fusion protein (e.g. see [0033]-[0035] and claim 2).
The Applicant also discloses that the term "GLP-1 RA" refers to a protein capable of binding to a receptor of glucagon-like peptide-1 (GLP-1) (e.g. see [0027]). The GLP-1 RA is not particularly limited as long as it selectively stimulates the GLP-1 receptor to have a signaling pathway similar to that of GLP-1, and may include, for example, GLP-1 and derivatives thereof. The GLP-1 derivatives may be prepared by way of one of substitution, addition, deletion, and modification of some amino acids of GLP-1, or any combination thereof. These GLP-1 derivatives may be any substance well known in the art, e.g., liraglutide, exendin-4, lixisenatide, dulaglutide, and albiglutide (e.g. see [0027]).
The Applicant also discloses that the GLP-1 RA may be linked to the anti-OSCAR antibody directly or via a linker (e.g. see [0037]). Any linking method commonly available in the art may be used without limitation in the fusion protein of the present invention, as long as the linkage does not change the structure or activity of the linked protein. The linker may be a peptidyl or non-peptidyl linker including 1 to 20 amino acids, without being limited thereto (e.g. see [0037]).
When given the broadest reasonable interpretation in light of specification, the fusion proteins of the instant invention are defined broadly to be any fusion protein that comprises any GLP-1 RA and any antibody that binds to OSCAR.
It is noted that the broadest claim (claim 1) does not indicate any specific structure for the genus of fusion proteins comprising a GLP-1 RA and an anti-OSCAR antibody.
Claim 2 limits the fusion protein to that which comprises an anti-OSCAR antibody comprising a VH and VL pair of SEQ ID NOs: a and 2. 3 and 4, and 5 and 6, respectively.
Claim 3 limits the fusion protein to that which comprises GLP-1 or a derivative thereof.
Claims 4-6 limit the fusion protein to that which further comprises a half-life-increasing substance. Claims 5 and 6 limit the half-life-increasing substance to an immunoglobulin Fc region. Claim 6 limits the immunoglobulin Fc region to that which comprises an N297A point mutation.
It is noted that only claim 7 recites sufficient structure for the claimed fusion protein.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., 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 applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, January 5, 2001, see especially page 1106 column 3). In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
It is noted that the claimed genus of GLP-1 RAs includes antibodies. As such, regarding anti-GLP-1 receptor and anti-OSCAR antibodies, artisans are well aware that knowledge of a given antigen (for instance the GLP-1 receptor or OSCAR) provides no information concerning the sequence/structure of antibodies that bind the given antigen. For example, Edwards et al. (J. Mol. Biol., 2003, 334:103-118) teach that over 1,000 different antibodies to a single protein can be generated, all with different sequences spanning almost the entire heavy and light chain germline repertoire (42/49 functional heavy chain germlines and 33 of 70 V-lambda and V-kappa light chain germlines, and with extensive diversity in the HCDR3 region sequences (that are generated by VDJ germline segment recombination) as well, see entire document).
As such, it does not seem possible to predict the sequence/structure of an antibody that binds a given antigen, as there does not appear to be any common or core structure present within all antibodies that gives rise to the function of antigen binding. Further, given data, such as that of Edwards et al., indicating the diversity of sequences in a population of antibodies that bind to a given antigen, no number of species appears to reasonably representative of the breadth of the genus of antibodies that bind the given antigen.
It should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway Jr et al., Immunology, 3rd Edition, 1997 Garland Publishing Inc., pages 3:1-3:11.see entire selection).
Thus, based upon the prior art, skilled artisans would reasonably understand that it is the structure of the CDRs within an antibody which gives rise to the functional property of antigen binding, the epitope to which said CDRs bind is an inherent property which appears to necessarily be present due to conservation of critical structural elements, namely the CDR sequences themselves.
This applies to the instant invention which is drawn to a genus fusion proteins which comprise a genus of GLP-1 RAs which encompass a subgenus of anti-GLP-1 receptor antibodies, and a genus of anti-OSCAR antibodies.
Regarding the subgenera of GLP-1 RAs that encompass “protein[s] capable of binding to a receptor of GLP-1”, the same logic applies. GLP-1 RAs comprising a protein capable of binding to a receptor of GLP-1 still require very precise structure in order confer agonist function.
Further regarding the structure of a GLP-1 RA-comprising fusion protein, Strohl (BioDrugs (2015) 29:215–239) teaches that the length and structure of the linker in a GLP-1 RA fusion protein was found to be a critical component of the design, because in the absence of the linker, the GLP-1 agonist activity is minimal (e.g. see page 220, right column, second paragraph).
In fact, Glaesner et al. (Diabetes Metab Res Rev 2010; 26: 287–296) teach a DPP-IV-protected GLP-1 analogue (V8-GLP-1)-IgG1 hinge region fusion with dramatically reduced in vitro activity (by ∼95%) compared to that of free V8-GLP-1 (e.g. see page 290, right column, third paragraph). Introducing optimized linker sequences as spacers between the GLP-1 moiety and the IgG-Fc hinge restored the full potency of the GLP-1 moiety, presumably by allowing sufficient conformational freedom and distance from the carrier domain for receptor interaction (e.g. see page 293, right column, third paragraph).
As noted above, the Applicant has only disclosed a single fusion protein (PF1803; SEQ ID NO: 7) which includes a GLP-1 RA and an anti-OSCAR antibody. Such a disclosure does not serve to provide sufficient written description of the claimed genus of fusion proteins comprising a GLP-1 RA and an anti-OSCAR antibody.
The disclosure does not identify any specific structural features or combination of features which give rise to the function of GLP-1 receptor agonism or binding to OSCAR. Additionally, there does not appear to be any reasonable shared structure present in the genus of recited fusion proteins which gives rise to their functional activity. Ultimately, identifying a fusion protein simply on the basis of GLP-1 receptor agonism and OSCAR binding rather than by identifying the sequence/structure, namely the CDRs and/or protein structure, of the GLP-1 RA, anti-OSCAR antibody, and the linker joining the two of the fusion protein in question is generally insufficient to provide written description.
The claims are drawn to a broad genus of fusion proteins which are functionally defined by their ability to agonize a GLP-1 receptor and bind OSCAR without reciting a corresponding structure expected to correlate with this ability as supported by Applicant’s disclosure.
Thus, there is insufficient written description for the breadth of fusion proteins comprising a GLP-1 RA and an anti-OSCAR antibody as currently claimed, which are distinct and diverse and do not share a common structure that contributes to a common ability to agonize a GLP-1 receptor and bind OSCAR.
Therefore, in view of the breadth of the claims and the limited disclosure, artisans would reasonably conclude that applicant was not in possession of the full breadth of fusion proteins comprising a GLP-1 RA and an anti-OSCAR antibody encompassed by the claims at the time the instant application was filed.
Amending claim 1 to recite: (1) the VH and VL pairs for the anti-OSCAR antibody from claim 2; (2) a specific amino acid sequence for the GLP-1 RA; and (3) a specific linker sequence for joining the GLP-1 RA and the anti-OSCAR antibody, such as SEQ ID NO: 7, would obviate this part of the rejection.
Enablement
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 8-13 are 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 a pharmaceutical composition for treating arthritis, a food composition for treating arthritis, a health functional food composition for treating arthritis, and a method of treating arthritis with the fusion protein comprising (1) a DPP-4 resistant GLP-1 analogue; (2) a carrier protein with limited target cell killing; and (3) a linker of sufficient structure and length to permit target binding; does not reasonably provide enablement for a pharmaceutical composition for preventing or treating arthritis, a food composition for preventing or treating arthritis, a health functional food composition for preventing or treating arthritis, and a method of preventing or treating arthritis with any fusion protein comprising any GLP-1 RA and an anti-OSCAR antibody.
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/or use the invention commensurate in scope with these claims.
The factors considered in determining whether a disclosure would require undue experimentation include:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP § 2164.01.
Nature of the invention/Breadth of the claims
Claims 8-10 are drawn to a pharmaceutical composition for preventing or treating arthritis.
Claim 11 is drawn to a food composition for preventing or treating arthritis.
Claim 12 is drawn to a health functional food composition for preventing or treating arthritis.
Claim 13 is drawn to method of preventing or treating arthritis comprising administering a pharmaceutical composition comprising a fusion protein comprising a GLP-1 RA and an anti-OSCAR antibody to an individual other than a human.
State of the prior art/Predictability of the art
Regarding the structure of the GLP-1 RA itself and in the context of the fusion protein, Strohl (BioDrugs (2015) 29:215–239) teaches that natural GLP-1 has a half-life in serum of about 2 min secondary to rapid inactivation by dipeptidyl peptidase-IV (DPP-IV/4) and excretion, so in its native form, GLP-1 could never be a drug (e.g. see page 220, paragraph spanning left and right columns and Abstract). Thus, analogues and long-acting formulations of analogues have been developed (e.g. see page 288, left column, second paragraph). Fusing GLP-1 to a larger ‘carrier’ moiety, hence slowing its in vivo clearance, would be expected to enhance pharmacokinetics (e.g. see page 288, left column, third paragraph). When GLP-1 is fused to the Fc domain of an immunoglobulin, the plasma half-life of GLP-1 is substantially prolonged (∼30 h) (e.g. see page 288, left column, third paragraph).
Strohl teaches several GLP-1 RA peptide-based drugs, all of which are DPP-4-resistant GLP-1 analogues and exhibit extended half-lives (e.g. see page 220, paragraph spanning left and right columns). For example, a DPP-4-resistant version of GLP-1 (V8-GLP-1)-Fc fusion protein possesses the activity of GLP-1 with a serum half-life of 4–5 days (e.g. see page 220, right column, second paragraph). A critical point for the GLP-1-Fc fusion protein design is that the Fc moieties were designed for minimal Fc activity, as opposed to using the Fc of an IgG1, which could result in effector function activity and potential killing activity toward the target cells possessing the GLP-1 receptor (GLP-1R) (e.g. see page 220, right column, second paragraph).
Minimal Fc activity is desirable if the cell surface targets are for inflammatory, metabolic, or biological indications other than cancer, such as arthritis (e.g. see Strohl and Strohl. 2012. Therapeutic antibody engineering: current and future advances driving the strongest growth area in the pharma industry. Cambridge: Woodhead Publishing Series in Biomedicine No. 11; Chapter 10 (Antibody Fc engineering for optimal antibody performance), paragraph spanning pages 240 and 241). The desired product profile will often require non-depletion (or non-killing) of the target cells while blocking the activity of the target receptor. For these cell-surface targets for which cell depletion via ADCC, ADCP, and/or CDC would be detrimental and potentially pose a safety risk, it is important to silence Fc functionality (e.g. see Strohl and Strohl. paragraph spanning pages 240 and 241). Strohl and Strohl also specifically teach the Fc-engineered antibody Tanezumab (RI-624) which was mutated to reduce effector function for treating osteoarthritis (e.g. see table 10.1).
Furthermore, Strohl teaches that the V8-GLP-1 is fused to the Fc of a human IgG4 (F234A/L235A) via a linker (e.g. see page 220, right column, second paragraph). The length and structure of the linker was found to be a critical component of the design, because in the absence of the linker, the GLP-1 agonist activity was minimal (e.g. see page 220, right column, second paragraph). Moreover, Glaesner et al. (Diabetes Metab Res Rev 2010; 26: 287–296) teach a DPP-IV-protected GLP-1 analogue (V8-GLP-1)-IgG1 hinge region fusion with dramatically reduced in vitro activity (by ∼95%) compared to that of free V8-GLP-1 (e.g. see page 290, right column, third paragraph). Introducing optimized linker sequences as spacers between the GLP-1 moiety and the IgG-Fc hinge restored the full potency of the GLP-1 moiety, presumably by allowing sufficient conformational freedom and distance from the carrier domain for receptor interaction (e.g. see page 293, right column, third paragraph).
The art ultimately teaches that given its short half-life, native GLP-1 is not suitable for therapeutic applications and requires modifications to extend its half-life by limiting its degradation by DPP-4 and its excretion. Current approaches to extending the half-life of GLP-1 include designing DPP-4 resistant analogues that are fused to carrier proteins, such as an Fc moiety, by a linker. The art clearly teaches that Fc moieties designed for minimal Fc activity are important for treating inflammatory diseases like arthritis in order to limit killing of target cells, and linkers need to be of sufficient length and structure to permit sufficient conformational freedom and distance from the carrier domain for receptor interaction.
Thus the art teaches that fusion proteins comprising a GLP-1 RA for treating arthritis require: (1) a DPP-4 resistant GLP-1 analogue; (2) a carrier protein with limited target cell killing; and (3) a linker sufficient length and structure to permit receptor interaction.
Working examples/Guidance in the specification
The Applicant has disclosed a single working example for treating arthritis with a fusion protein comprising a GLP-1 RA and an anti-OSCAR antibody (e.g. see examples 3-5 spanning pages 13-15). The Applicant on applied a single GLP-1 RA-anti-OSCAR antibody fusion protein (PF1803; SEQ ID NO: 7) in this method.
It is noted that SEQ ID NO: 7 has the formula: GLP-1-Fc-VH-VL, wherein the GLP-1 (amino acids 1-31) is a dipeptidyl peptidase-IV (DPP-IV)-protected GLP-1 analogue (V8-GLP-1) (e.g. see Glaesner et al. Diabetes Metab Res Rev 2010; 26: 287–296, figure caption for FIG. 1C), the Fc is SEQ ID NO: 9 which comprises as N297A point mutation which reduces effector function, the VH is SEQ ID NO: 5, and the VL is SEQID NO: 6. It is also noted that there is a 29 amino acid linker between the GLP-1 analogue and the Fc mutant (amino acids 32-60) which comprises a IgG1 hinge region (amino acids 43-60). See sequence alignment above in written description rejection.
The Applicant also discloses that the term "GLP-1 RA" refers to a protein capable of binding to a receptor of glucagon-like peptide-1 (GLP-1) (e.g. see [0027]). The GLP-1 RA is not particularly limited as long as it selectively stimulates the GLP-1 receptor to have a signaling pathway similar to that of GLP-1, and may include, for example, GLP-1 and derivatives thereof. The GLP-1 derivatives may be prepared by way of one of substitution, addition, deletion, and modification of some amino acids of GLP-1, or any combination thereof. These GLP-1 derivatives may be any substance well known in the art, e.g., liraglutide, exendin-4, lixisenatide, dulaglutide, and albiglutide (e.g. see [0027]).
The Applicant also discloses that the GLP-1 RA may be linked to the anti-OSCAR antibody directly or via a linker (e.g. see [0037]). Any linking method commonly available in the art may be used without limitation in the fusion protein of the present invention, as long as the linkage does not change the structure or activity of the linked protein. The linker may be a peptidyl or non-peptidyl linker including 1 to 20 amino acids, without being limited thereto (e.g. see [0037]).
Amount of experimentation necessary
The instant specification discloses a single working example for treating arthritis with a single fusion protein comprising V8-GLP-1, a 29 amino acid linker comprising a IgG1 hinge region, a IgG1 Fc N297A variant (SEQ ID NO: 9), and an anti-OSCAR scFv comprising SEQ ID NOs: 5 and 6.
The claimed products and method encompass those for preventing or treating arthritis with any fusion protein comprising any GLP-1 RA and an anti-OSCAR antibody. There is insufficient objective evidence that the disclosed products and method for treating arthritis can be extrapolated to provide guidance and direction for the claimed products and method for preventing or treating arthritis with any fusion protein comprising any GLP-1 RA and an anti-OSCAR antibody.
Thus, based on the content of the disclosure in view of the prior art regarding fusion proteins comprising a GLP-1 RA for treating arthritis requiring: (1) a DPP-4 resistant GLP-1 analogue; (2) a carrier protein with limited target cell killing; and (3) a linker sufficient length and structure to permit receptor interaction, a skilled artisan, through extensive trial-and-error experimentation, would have to identify GLP-1 RA and anti-OSCAR antibody-comprising fusion proteins with GLP-1 agonistic function and then use them in the claimed products and method for preventing or treating arthritis with a reasonable expectation of success.
This quantity of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the products and method for the breadth of what is claimed. A person of ordinary skill in the art would have to perform undue experimentation in order to use a product or method for preventing or treating arthritis with any fusion protein comprising any GLP-1 RA and an anti-OSCAR antibody commensurate in scope with the breadth of the claims.
Furthermore, regarding the claim limitation of “preventing” in claims 8-13, the burden of enabling the prevention of a disease (i.e. the need for additional testing) would be greater than that of enabling a treatment due to the need to screen those subjects susceptible to such diseases and the difficulty of proof that the administration of the drug was the agent that acted to prevent the condition. Further, the specification does not provide guidance as to how one skilled in the art would go about screening those patients susceptible to arthritis within the scope of the presently claimed invention. Nor is sufficient guidance provided as to a specific protocol to be utilized in order to prove the efficacy of the presently claimed fusion protein in preventing arthritis.
While the specification discloses an example of treating arthritis with the instantly claimed protein fusion, the treatment was only given to the subjects after arthritis was induced not prior. Therefore, the specification at most discloses treating arthritis with the instantly claimed protein fusion but not preventing arthritis.
Thus, the specification does not enable one of ordinary skill in the art to use what is claimed and therefore claims 8-13 are rejected under 35 U.S.C. 112(a).
Amending claims 8 and 11-13 to delete the term “preventing” and to include that the fusion protein comprises (1) a DPP-4 resistant GLP-1 analogue; (2) a carrier protein with limited target cell killing; and (3) a linker sufficient structure and length to permit target binding, such as SEQ ID NO: 7, would obviate this part of the rejection.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 103
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, and 8-13 are rejected under 35 U.S.C. 103 as being unpatentable over Glaesner et al. 2010 (Diabetes Metab Res Rev. 26: 287–296) in view of Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14, an IDS reference filed 06/02/2023), Park et al. 2020 (Nat Comm. 11: 4343, 1-11, an IDS reference filed 06/02/2023), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595).
Independent claim 1 is drawn to a fusion protein comprising a glucagon-like peptide-1 (GLP-1) RA and an anti-osteoclast-associated receptor (OSCAR) antibody.
Dependent claim 3 limits the GLP-1 RA to GLP-1 or a derivative thereof.
Dependent claim 4 recites that the fusion protein further comprises a half-life-increasing substance.
Dependent claim 5 limits the half-life-increasing substance to an immunoglobulin Fc region.
Dependent claims 8-10 are drawn to pharmaceutical composition for preventing or treating arthritis, comprising the fusion protein according claim 1 as an active ingredient. Claim 9 limits the arthritis to degenerative arthritis or rheumatoid arthritis. Claim 10 recites that the pharmaceutical composition delays cartilage destruction or relieves pain.
Dependent claim 11 is drawn to a food composition for preventing or alleviating arthritis comprising the fusion protein according claim 1 as an active ingredient.
Dependent claim 12 is drawn to a health functional food composition for preventing or alleviating arthritis comprising the fusion protein according claim 1 as an active ingredient.
Dependent claim 13 is drawn to a method of preventing or treating arthritis, the method comprising administering the pharmaceutical composition of claim 8 to an individual other than a human.
Regarding claims 1 and 3-5, Glaesner et al. teach a fusion protein comprising a DPP-IV-protected GLP-1 analogue (V8-GLP-1) and a modified IgG4 Fc (LY2189265) with extended pharmacokinetics and activity (e.g. see page 290, right column, third paragraph). Fusing GLP-1 to a larger ‘carrier’ moiety, such as the modified IgG4 Fc is expected to enhance pharmacokinetics (half-life) by slowing its in vivo clearance (e.g. see page 288, left column, third paragraph). When GLP-1 was fused to the Fc domain of an immunoglobulin, the plasma half-life of GLP-1 was substantially prolonged (∼30 h) (e.g. see page 288, left column, third paragraph).
Glaesner et al. do not teach that the fusion protein also comprises an anti-OSCAR antibody; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; or a method of preventing or treating arthritis.
Chen et al. 2018 teach that expression of GLP-1R is decreased in degenerative cartilage, indicating the dysfunction of GLP-1R pathway during the process of osteoarthritis (OA) (e.g. see paragraph spanning pages 9 and 10). Chen et al. 2018 also teach that activation of GLP-1R markedly reduces the levels of pro-apoptotic Bax and cleaved-caspase3, and increases anti-apoptotic Bcl-2 in IL-1β-induced chondrocytes, indicating that GLP-1R may be a potential target for the treatment of OA (e.g. see paragraph spanning pages 9 and 10). Chen et al. 2018 also teach that the GLP-1R agonist, liraglutide, exerts a therapeutic effect in a rat OA model (e.g. see page 10, paragraph spanning the left and right columns). Ultimately, Chen et al. 2018 teach the anti-apoptotic and anti-inflammatory effects of GLP-1R activation in chondrocytes, in vivo and in vitro, which demonstrate that GLP-1R may be a novel target for the treatment of OA (e.g. see page 10, right column, fourth paragraph).
Regarding claim 9, Chen et al. 2018 also teach that OA is a prevalent progressive and degenerative joint disease (e.g. see page 1, paragraph spanning left and right columns).
Park et al. teach that OSCAR is expressed in myeloid cells, including monocytes, macrophages, dendritic cells, and osteoclasts (e.g. see page 5, paragraph spanning left and right columns). Osteoclasts can bind to collagens exposed on bone surfaces to promote osteoclast formation (e.g. see page 5, paragraph spanning left and right columns). OSCAR levels increase during OA pathogenesis in human and mouse articular cartilages (e.g. see page 5, left column, second paragraph). Oscar deficiency in mice prevents the development of OA and lowers the expression levels of OA catabolic factors and extracellular matrix molecules. OSCAR regulates chondrocyte apoptosis during OA pathogenesis. Furthermore, OSCAR-Fc protein inhibited OA-induced cartilage destruction in mouse models, suggesting that OSCAR may represent a therapeutic target against OA (e.g. see page 5, left column, second paragraph).
Chen et al. 2012 teach that bifunctional fusion proteins, constructed by fusing the genes of two proteins together, combine the functions of the parent proteins in order to improve their PK and PD properties and introduce novel approaches in drug delivery or targeting (e.g. see paragraph spanning pages 1 and 2). Chen et al. 2012 also teach a class of fusions proteins designed to specifically target a functional domain to a disease site using targeting moieties, wherein the targets display favorable biodistribution (e.g. see page 6, second paragraph). These bifunctional fusion proteins with targeting effect can include functional domain fused to an antibody, wherein the antibody targets the functional domain to a specific site (e.g. see Table 4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Glaesner et al. to incorporate the teachings of Chen et al. 2018, Park et al., and Chen et al. 2012 to include teach that the fusion protein also comprises an anti-OSCAR antibody; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; and a method of preventing or treating arthritis. This is because GLP-1 receptor agonism may be a novel target for the treatment of OA (Chen et al. 2018), OSCAR may represent a therapeutic target against OA (Park et al.), and bifunctional fusion proteins combine the functions of the parent proteins in order to improve their PK and PD properties and are useful for targeting a functional domain to a disease site (Chen et al. 2012).
Given the anti-apoptotic and anti-inflammatory effects of GLP-1R activation in chondrocytes, that OSCAR expression is increased in OA and regulates chondrocyte apoptosis during OA pathogenesis, that both GLP-1 R and OSCAR are promising targets for treating OA, and that bifunctional fusion proteins are intended combine the functions of the parent proteins and are useful for targeting a functional domain to a disease site; it would have been obvious to a skilled artisan, with the goal of designing a bifunctional fusion protein for treating arthritis, to modify the GLP-1 RA fusion protein taught by Glaesner et al. to further include an anti-OSCAR antibody with a reasonable expectation of success.
Both the dysfunction of the GLP-1 receptor and the OSCAR protein are implicated in chondrocyte apoptosis and contribute to OA. A fusion protein comprising a GLP-1 RA (functional domain) and an anti-OSCAR antibody (targeting moiety/functional) would be expected to allow for targeted delivery of the GLP-1 RA to the OSCAR-overexpressing chondrocytes, thus, permitting targeted GLP-1 receptor activation on said chondrocytes. Furthermore, the anti-OSCAR antibody would be expected to function as more than just a targeting moiety and may also exhibit a therapeutic effect on OA similar to the GLP-1 RA.
Regarding claims 8-13, given the desire for treating OA in a patient, it would have been obvious to a skilled artisan to use the GLP-1 RA-anti-OSCAR fusion protein as taught by Glaesner et al. in view of Chen et al. 2018, Park et al., and Chen et al. 2012 in a pharmaceutical composition, a food composition, a health functional food composition, and a method for treating arthritis with a reasonable expectation of success.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 6 is rejected under 35 U.S.C. 103 as being unpatentable over Glaesner et al. 2010 (Diabetes Metab Res Rev. 26: 287–296) in view of Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14), Park et al. 2020 (Nat Comm. 11: 4343, 1-11), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595), as applied to claims 1, 4, and 5, and further in view of Strohl and Strohl. 2012. (Therapeutic antibody engineering. Cambridge: Woodhead Publishing Series in Biomedicine No. 11; Chapter 10).
Dependent claim 6 limits the immunoglobulin Fc region to those that comprise an N297A point mutation.
The combined teachings of Glaesner et al. in view of Chen et al. 2018, Park et al., and Chen et al. 2012 pertaining to claims 1, 4, and 5, and the rationale for combining them are outlined in the 103 rejection above.
Glaesner et al. also teach that the Fc region was derived from IgG4 instead of IgG1 to reduce potential complement-dependent and antibody-dependent cell-mediated cytotoxicity (ADCC) conferred by native IgG1 Fc moieties (e.g. see page 290, right column, third paragraph). The modified IgG4 Fc was optimized at two selected positions (F234A and L235A) to reduce interaction with high-affinity Fc receptors, which resulted in significant reduction of dose-dependent cytotoxicity over the IgG1 version in an ADCC assay (e.g. see page 290, right column, third paragraph).
The combined reference teachings do not teach that the immunoglobulin Fc region is an IgG1 Fc region comprising an N297A point mutation.
Strohl and Strohl teach that minimal Fc activity is desirable if the cell surface targets are for inflammatory, metabolic, or biological indications other than cancer, such as arthritis (e.g. see paragraph spanning pages 240 and 241). The desired product profile will often require non-depletion (or non-killing) of the target cells while blocking the activity of the target receptor. For these cell-surface targets for which cell depletion via ADCC, ADCP, and/or CDC would be detrimental and potentially pose a safety risk, it is important to silence Fc functionality (e.g. see paragraph spanning pages 240 and 241). Strohl and Strohl also specifically teach the Fc-engineered antibody Tanezumab (RI-624) which was mutated to reduce effector function for treating osteoarthritis (e.g. see table 10.1).
Strohl and Strohl also teach that N297A-mutant non-glycosylated IgGs have been shown to have substantially decreased binding to FcγRs resulting in decreased ADCC and ADCP (e.g. see page 240, second paragraph; and Table 10.4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the combined teachings of Glaesner et al. in view of Chen et al. 2018, Park et al., and Chen et al. 2012 as applied to claims 1, 4, and 5 and incorporate the teachings of Strohl and Strohl to include that that the immunoglobulin Fc region an IgG1 Fc region comprising an N297A point mutation. This is because the N297A mutation in an IgG1 Fc is well known to decrease ADCC and ADCP.
Given the desire for reducing ADCC of the GLP-1 RA fusion protein (Glaesner et al.), especially for treating biological indications that are not cancer, such as arthritis (Strohl and Strohl) and that N297A-mutant IgGs have been shown to have substantially decreased ADCC and ADCP; it would have been obvious to a skilled artisan to modify the IgG Fc region of the GLP-1 RA fusion protein taught by Glaesner et al. in view of Chen et al. 2018, Park et al., and Chen et al. 2012, to include an IgG1 Fc region comprising an N297A point mutation with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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, and 8-13 are provisionally rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-7 of U.S. Application No. 18/862,754 (the ‘754 Application) in view Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14), Park et al. 2020 (Nat Comm. 11: 4343, 1-11), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595).
The instant claims are drawn to a fusion protein comprising a glucagon-like peptide-1 (GLP-1) RA and an anti-osteoclast-associated receptor (OSCAR) antibody; a pharmaceutical composition for preventing or treating arthritis; a food composition for preventing or alleviating arthritis; a health functional food composition for preventing or alleviating arthritis; and a method of preventing or treating arthritis.
The claims in the ‘754 Application are drawn to a fusion protein comprising a GLP-1, an immunoglobulin Fc region, and an IGF-1; a pharmaceutical composition for the prevention or treatment of a neurological disease; and a method for preventing or treating a neurological disease.
The claims in the ‘754 Application differ from the instant invention by not reciting that the fusion protein comprises an anti-OSCAR antibody; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; or a method of preventing or treating arthritis.
The teachings of Chen et al. 2018, Park et al., and Chen et al. 2012 are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘754 Application to incorporate the teachings of Chen et al. 2018, Park et al., and Chen et al. 2012 to include teach that the fusion protein comprises an anti-OSCAR antibody; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; and a method of preventing or treating arthritis. This is because GLP-1 receptor agonism may be a novel target for the treatment of OA (Chen et al. 2018), OSCAR may represent a therapeutic target against OA (Park et al.), and bifunctional fusion proteins combine the functions of the parent proteins in order to improve their PK and PD properties and are useful for targeting a functional domain to a disease site (Chen et al. 2012).
Given the anti-apoptotic and anti-inflammatory effects of GLP-1R activation in chondrocytes, that OSCAR regulates chondrocyte apoptosis during OA pathogenesis, that both GLP-1 R and OSCAR are promising targets for treating OA, and that bifunctional fusion proteins are intended combine the functions of the parent proteins and are useful for targeting a functional domain to a disease site; it would be obvious to a skilled artisan, with the goal of designing a bifunctional fusion protein for treating arthritis, to modify the GLP-1 fusion protein taught by the ‘754 Application to further include an anti-OSCAR antibody with a reasonable expectation of success.
Both the dysfunction of the GLP-1 receptor and the OSCAR protein are implicated in chondrocyte apoptosis and contribute to OA. A fusion protein comprising a GLP-1 RA (functional domain) and an anti-OSCAR antibody (targeting moiety/functional) would be expected to allow for targeted delivery of the GLP-1 RA to the OSCAR-expressing chondrocytes, thus, permitting targeted GLP-1 receptor activation on said chondrocytes. Furthermore, the anti-OSCAR antibody would be expected to function as more than just a targeting moiety and may also exhibit a therapeutic effect on OA similar to the GLP-1 RA.
Regarding claims 8-13, given the desire for treating OA in a patient, it would be obvious to a skilled artisan to use the GLP-1 RA-anti-OSCAR fusion protein as taught by the ‘754 Application in view of Chen et al. 2018, Park et al., and Chen et al. 2012 in a pharmaceutical composition, a food composition, a health functional food composition, and a method for treating arthritis.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
As such, the claims in the ‘754 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection since the claims are in fact not patented.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-7 of U.S. Application No. 18/862,754 (the ‘754 Application) in view Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14), Park et al. 2020 (Nat Comm. 11: 4343, 1-11), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595), as applied to claims 1, 4, and 5, and further in view of Strohl and Strohl. 2012. (Therapeutic antibody engineering. Cambridge: Woodhead Publishing Series in Biomedicine No. 11; Chapter 10).
The combined teachings of the ‘754 Application in view of Chen et al. 2018, Park et al., and Chen et al. 2012 pertaining to claims 1, 4, and 5, and the rationale for combining them are outlined in the NSDP rejection above.
The combined teachings do not teach that the immunoglobulin Fc region is an IgG1 Fc region comprising an N297A point mutation.
The teachings of Strohl and Strohl are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the combined teachings of the ‘754 Application in view of Chen et al. 2018, Park et al., and Chen et al. 2012 as applied to claims 1, 4, and 5 and incorporate the teachings of Strohl and Strohl to include that that the immunoglobulin Fc region an IgG1 Fc region comprising an N297A point mutation. This is because the N297A mutation in an IgG1 Fc is well known to decrease ADCC and ADCP.
Given the desire for reducing the effector function or a product for treating biological indications that are not cancer, such as arthritis (Strohl and Strohl) and that N297A-mutant IgGs have been shown to have substantially decreased ADCC and ADCP; it would be obvious to a skilled artisan to modify the IgG Fc region of the GLP-1 protein taught by the ‘754 Application in view of Chen et al. 2018, Park et al., and Chen et al. 2012, to include an IgG Fc region comprising an N297A point mutation with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
As such, the claims in the ‘754 Application would render the instant claims obvious.
This is a provisional nonstatutory double patenting rejection since the claims are in fact not patented.
Claims 1, 3-5, and 8-13 are rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-6 of U.S. Patent No. 10,993,993 (the ‘993 Patent) in view Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14), Park et al. 2020 (Nat Comm. 11: 4343, 1-11), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595).
The instant claims are drawn to a fusion protein comprising a glucagon-like peptide-1 (GLP-1) RA and an anti-osteoclast-associated receptor (OSCAR) antibody; a pharmaceutical composition for preventing or treating arthritis; a food composition for preventing or alleviating arthritis; a health functional food composition for preventing or alleviating arthritis; and a method of preventing or treating arthritis.
The claims in the ‘993 Patent are drawn to a method for treating muscle atrophy or sarcopenia, comprising administering an effective amount of a pharmaceutical composition comprising glucagon-like peptide-1 (GLP-1) or a GLP-1 fragment to a subject having muscle atrophy or sarcopenia, wherein the GLP-1 or the GLP-1 fragment includes the amino acid sequence of SEQ ID NO: 4.
The claims in the ‘993 Patent differ from the instant invention by not reciting a GLP-1 RA-an anti-OSCAR antibody fusion protein; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; or a method of preventing or treating arthritis.
The teachings of Chen et al. 2018, Park et al., and Chen et al. 2012 are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the claims in the ‘993 Patent to incorporate the teachings of Chen et al. 2018, Park et al., and Chen et al. 2012 to include a GLP-1 RA-an anti-OSCAR antibody fusion protein; that the fusion protein is part of a pharmaceutical composition, a food composition, or a health functional food composition for preventing or treating arthritis; and a method of preventing or treating arthritis. This is because GLP-1 receptor agonism may be a novel target for the treatment of OA (Chen et al. 2018), OSCAR may represent a therapeutic target against OA (Park et al.), and bifunctional fusion proteins combine the functions of the parent proteins in order to improve their PK and PD properties and are useful for targeting a functional domain to a disease site (Chen et al. 2012).
Given the anti-apoptotic and anti-inflammatory effects of GLP-1R activation in chondrocytes, that OSCAR regulates chondrocyte apoptosis during OA pathogenesis, that both GLP-1 R and OSCAR are promising targets for treating OA, and that bifunctional fusion proteins are intended combine the functions of the parent proteins and are useful for targeting a functional domain to a disease site; it would be obvious to a skilled artisan, with the goal of designing a bifunctional fusion protein for treating arthritis, to modify the GLP-1 fusion protein taught by the ‘993 Patent to further include an anti-OSCAR antibody with a reasonable expectation of success.
Both the dysfunction of the GLP-1 receptor and the OSCAR protein are implicated in chondrocyte apoptosis and contribute to OA. A fusion protein comprising a GLP-1 RA (functional domain) and an anti-OSCAR antibody (targeting moiety/functional) would be expected to allow for targeted delivery of the GLP-1 RA to the OSCAR-expressing chondrocytes, thus, permitting targeted GLP-1 receptor activation on said chondrocytes. Furthermore, the anti-OSCAR antibody would be expected to function as more than just a targeting moiety and may also exhibit a therapeutic effect on OA similar to the GLP-1 RA.
Regarding claims 8-13, given the desire for treating OA in a patient, it would be obvious to a skilled artisan to use the GLP-1 RA-anti-OSCAR fusion protein as taught by the ‘993 Patent in view of Chen et al. 2018, Park et al., and Chen et al. 2012 in a pharmaceutical composition, a food composition, a health functional food composition, and a method for treating arthritis.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
As such, the claims in the ‘993 Patent would render the instant claims obvious.
Claim 6 is provisionally rejected on the ground of nonstatutory double patenting (NSDP) as being unpatentable over claims 1-6 of U.S. Patent No. 10,993,993 (the ‘993 Patent) in view Chen et al. 2018 (Cell Death and Disease. 9:212, 1-14), Park et al. 2020 (Nat Comm. 11: 4343, 1-11), and Chen et al. 2012 (Expert Opin Drug Metab Toxicol. 8(5): 581–595), as applied to claims 1, 4, and 5, and further in view of Strohl and Strohl. 2012. (Therapeutic antibody engineering. Cambridge: Woodhead Publishing Series in Biomedicine No. 11; Chapter 10).
The combined teachings of the ‘993 Patent in view of Chen et al. 2018, Park et al., and Chen et al. 2012 pertaining to claims 1, 4, and 5, and the rationale for combining them are outlined in the NSDP rejection above.
The combined teachings do not teach that the GLP-1 RA-anti-OSCAR fusion protein comprises an immunoglobulin Fc region is an IgG1 Fc region comprising an N297A point mutation.
The teachings of Strohl and Strohl are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the combined teachings of the ‘993 Patent in view of Chen et al. 2018, Park et al., and Chen et al. 2012 as applied to claims 1, 4, and 5 and incorporate the teachings of Strohl and Strohl to include that that the GLP-1 RA-anti-OSCAR fusion protein comprises an immunoglobulin Fc region is an IgG1 Fc region comprising an N297A point mutation. This is because the N297A mutation in an IgG1 Fc is well known to decrease ADCC and ADCP.
Given the desire for reducing the effector function or a product for treating biological indications that are not cancer, such as arthritis (Strohl and Strohl) and that N297A-mutant IgGs have been shown to have substantially decreased ADCC and ADCP; it would be obvious to a skilled artisan to modify the GLP-1 RA-anti-OSCAR fusion protein taught by the ‘993 Patent in view of Chen et al. 2018, Park et al., and Chen et al. 2012 to include an IgG Fc region comprising an N297A point mutation with a reasonable expectation of success.
Combining prior art elements according to known methods to yield predictable results is obvious to one of ordinary skill in the art (see MPEP § 2143(A)). From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
As such, the claims in the ‘993 Patent would render the instant claims obvious.
Allowable Subject Matter
Claim 7 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
It is noted that fusion protein comprising a GLP-1 RA and an anti-OSCAR antibody, wherein the fusion protein comprises SEQ ID NO: 7 is free of the prior art.
It is also noted that an anti-OSCAR antibody comprising VH and VL amino acid sequences of SEQ ID NOs: 1 and 2, 3 and 4, or 5 and 6, respectively, is free of the prior art.
Conclusion
Claims 1-6 and 8-13 are rejected.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641