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 .
Election/Restrictions
Applicant’s election without traverse of the species Compound 5 in the reply filed on February 10, 2026, is acknowledged.
The following determinations are made based on the examination and search conducted for this Office action:
Elected species Compound 5 and additional species Compounds 1-3, 6, 9-10, 12, and 15 are obvious over the prior art; and
Species Compounds 18, 21-45, and 49-57 and the sub-genus in claims 6 and 16 are free of the prior art.
Because the elected species is rejected, the search was not extended further to include species Compounds 4, 7-8, 11, 13-14, 16-17, 19-20, or 46-48 (see MPEP 808.02).
Claim Rejections - 35 USC § 103
In the event the determination of the statutes 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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
I. Obviousness of Compounds 1-3, 5, 9, and 15
Claims 1-5, 7, 9-13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over DiMarchi et al. (US 9,062,124 B2) in view of Just et al. (WO 2015/067716 A1), DiMarchi et al. (WO 2011/143208 A1) and DiMarchi et al. (WO 2012/088116 A2).
Determining the scope and contents of the prior art.
DiMarchi et al. (US 9,062,124 B2) teach peptides that exhibit agonist activity against three receptors, the glucagon-like peptide-1 receptor (GLP1R), the glucose-dependent insulinotropic peptide receptor (GIPR), and the glucagon receptor (GcgR) (i.e. triagonist or triple or triagonal agonist peptides). The triple agonist peptides include:
MT-252 (SEQ ID:107) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSC-NH2
MT-255 (SEQ ID:108) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSC(PEG40K)
MT-277 (SEQ ID:123) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSK(14C ACYL)
MT-278 (SEQ ID:124) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSK(16C ACYL)
MT-279 (SEQ ID:125) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSK(18C ACYL)
MT-280 (SEQ ID:126) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSK-NH2
MT-323 (SEQ ID:148) YXQGTFTSDYSIYLDKQAAXEFVNWLLAGGPSSGAPPPSK(8C ACYL)
wherein X is Aib. The peptides listed above are identical to each other at positions 1-39 but differ in the presence or absence of a substituent attached to a Cys or Lys side chain at position 40. See Example 24 (especially at col 81, lines 13-22, and Table 2), and Example 25 (especially at col 83, lines 27-33, and Table 3). DiMarchi et al. (US 9,062,124 B2) teach that the triple agonist peptides MT-277, MT-278, and MT-279, which are identical except for the size of the fatty acyl group attached to the epsilon amino group of Lys-40, reduce blood glucose and body weight of subjects in vivo (see Examples 31 and 36 and Figures 27-28 and 35).
Ascertaining the differences between the prior art and the claims at issue.
The instant claims include triple agonist peptides Compounds 1-3, 5, and 9, which have the same base amino acid sequence as positions 1-39 of the MT-252, MT-255, MT-277, MT-278, MT-279, MT-280, and MT-323 triple agonist peptides of DiMarchi et al. (US 9,062,124 B2) with the following differences:
Instead of the fatty acyl substituent, the instant claims require a fatty diacid A covalently attached to the peptide by groups B-C (i.e. substituent Chem 6 or Chem 12); and
Instead of attachment of the substituent at position 40 (lysine or cysteine), the instant claims require that the substituent be attached at a lysine at position 16, 17, or 21.
In addition, the instant claims include triple agonist peptide Compound 15 with one additional difference:
Substitution of aspartic acid with glutamic acid at position 15.
Resolving the level of ordinary skill in the pertinent art.
Just et al. teach peptides that exhibit agonist activity against three receptors, the glucagon-like peptide-1 receptor (GLP1R), the glucose-dependent insulinotropic peptide receptor (GIPR), and the glucagon receptor (GcgR) (i.e. triagonist or triple agonist peptides) and their use in the treatment of metabolic disorders (abstract). The triple agonist peptides contain a lipophilic substituent attached to the peptide via an epsilon amino group of at position 16 or 17 (p. 3, line 13 - p. 4, line 20; p. 16, line 20 - p. 17, line 2). Just et al. teach that the lipophilic substituent binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the peptide from enzymatic degradation and renal clearance, thereby enhancing the half-life of the peptides (p. 16, lines 25-28). Just et al. teach that the lipophilic substituent may be identical to instant Chem 6 or Chem 12 (see p. 26, line 11 (i), and p. 27, line 5 (v)). See species Compounds 33-34, 38, 40-41, 44-45, 49, 51-52 in Table 1, each of which contain Chem 6 or Chem 12 attached to the peptide via the epsilon amino group of a lysine. The species exhibit triple agonist activity (Table 2b). In addition, Just et al. teach that position 15 can be aspartic acid or glutamic acid (p. 3, line 33).
DiMarchi et al. (WO 2011/143208 A1) also teach triple agonist peptides with activity on the GLP1, GIPR, and glucagon receptors and their use in the treatment of metabolic disorders (para. [0231]). DiMarchi et al. (WO 2011/143208 A1) teach that the triple agonist peptides may contain a lipophilic substituent attached to the peptide via an epsilon amino group of lysine at position 16, 17, or 21 (para. [0244]).
DiMarchi et al. (WO 2012/088116 A2) also teach triple agonist peptides with activity on the GLP1, GIPR, and glucagon receptors and their use in the treatment of metabolic disorders (para. [0062]-[0064]). DiMarchi et al. (WO 2012/088116 A2) reduce to practice a triple agonist containing a lipophilic group attached to the epsilon amino group of lysine at position 16 (SEQ ID NO: 153; Table 10, p. 183)
Considering objective evidence present in the application indicating obviousness or nonobviousness.
Table 1 of the specification provides a comparison between MT-278 of DiMarchi et al. (US 9,062,124 B2) and compounds containing Chem 6 substituent at various attachment sites (Lys40, Lys12, Lys13, Lys14, Lys16, Lys17, Lys20, Lys21, Lys24, Lys29, and Lys35). The specification states that the results in Table 1 indicate that placement of the Chem 6 is preferred at positions 16, 17, and 21 over all of the other tested positions (p. 77, lines 5-15). Table 2 of the specification demonstrates that each of the compounds recited in claim 10 exhibits triple agonist activity. These results are expected in view of the prior art of Just et al., which teaches that Chem 6 and Chem 12 can be used as a substituent to extend the half-life of triple agonist peptides, and of Just et al., DiMarchi et al. (WO 2011/143208 A1), and DiMarchi et al. (WO 2012/088116 A2), which teach that the substituent can be attached to positions 16, 17, and 21 in triple agonist peptides.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the lipophilic substituent Chem 6 or Chem 12 at a lysine at position 16 or 17 as taught by Just et al., or position or position 16, 17, or 21 as taught by DiMarchi et al. (WO 2011/143208 A1) for the lipophilic substituent at position 40 in the triple agonist peptides taught by DiMarchi et al. to yield instant Compounds 1-2, 5, and 9. It would have been further obvious to substitute a glutamic acid for an aspartic acid at position 15 as taught by Just et al. to yield instant Compound 15. The rationale for obviousness is simple substitution of one known element for another to obtain predictable results (MPEP § 2143.01(B)). The relevant findings for this rationale are as follows.
(1) The prior art contained a product which differed from the claimed device by the substitution of some element with other elements. In the instant case, the primary reference teaches GLP-1/GIP/Gcg receptor triple agonists which differ from the claimed compounds by the substitution of the substituent Chem 6 or Chem 12 at a lysine at position 16, 17, or 21 for the substituent at position 40 (plus for Compound 15 the substitution of a glutamic acid for an aspartic acid at position 15). Therefore, prior art contained a product which differed from the claimed product by the substitution of some element with other elements.
(2) The substituted components and their functions were known in the art. Just et al. teach a substituent identical to instant Chem 6 or Chem 12 (see p. 26, line 11 (i), and p. 27, line 5 (v)). See species Compounds 33-34, 38, 40-41, 44-45, 49, 51-52 in Table 1, each of which contain Chem 6 or Chem 12 attached to the peptide via the epsilon amino group of a lysine. Just et al. teach triple agonist peptides with a substituent attached to the epsilon amino group of lysine at position 16 or 17 (p. 3, line 13 - p. 4, line 20; p. 16, line 20 - p. 17, line 2). DiMarchi et al. (WO 2011/143208 A1) teach that the substituent can be attached to lysine at position 16, 17, or 21 (para. [0244]). The function of substituent is known in the art because Just et al. teach that the it binds plasma proteins (e.g. albumin) in the blood stream, thus shielding the peptide from enzymatic degradation and renal clearance, thereby enhancing the half-life of the peptides (p. 16, lines 25-28). Regarding Compound 15, Just et al. teach that position 15 can be aspartic acid or glutamic acid, which are amino acids that differ by only one CH2 group in the side chain but otherwise share the same negatively charged carboxyl group (p. 3, line 33). Therefore, the substituted components and their functions were known in the art.
(3) One of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. One of ordinary skill in the art would expect that the Chem 6 and Chem 12 at lysine 16, 17, and 21 performs the function of binding plasma proteins (e.g. albumin) in the blood stream, thus shielding the peptide from enzymatic degradation and renal clearance, thereby enhancing the half-life of the peptide in the combination because this is the function it performs in the prior art of Just et al. In addition, Just et al. demonstrate that the peptides containing Chem 6 or Chem 12 and with modifications at lysine 16 or 17 exhibit triple agonist activity (Table 2b). Furthermore, DiMarchi et al. (WO 2012/088116 A2) reduce to practice a single triple agonist containing a lipophilic group attached to the epsilon amino group of lysine at position 16 (SEQ ID NO: 153; Table 10, p. 183), showing that modification at this position does not block triple agonist activity. DiMarchi et al. (WO 2011/143208 A1) teach that the substituent can be attached to lysine at position 16, 17, or 21 (para. [0244]). Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. Table 1 of the specification provides a comparison between MT-278 of DiMarchi et al. (US 9,062,124 B2) and compounds containing Chem 6 substituent at various attachment sites (Lys40, Lys12, Lys13, Lys14, Lys16, Lys17, Lys20, Lys21, Lys24, Lys29, and Lys35). The specification states that the results in Table 1 indicate that placement of the Chem 6 is preferred at positions 16, 17, and 21 over all of the other tested positions (p. 77, lines 5-15). Table 2 of the specification demonstrates that each of the compounds recited in claim 10 exhibits triple agonist activity. These results are expected in view of the prior art of Just et al., which teaches that Chem 6 and Chem 12 can be used as a substituent to extend the half-life of triple agonist peptides, and of Just et al., DiMarchi et al. (WO 2011/143208 A1), and DiMarchi et al. (WO 2012/088116 A2), which teach that the substituent can be attached to positions 16, 17, and 21 in triple agonist peptides.
The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
Compounds 1-3, 5, 9, and 15 are encompassed by claims 1-5, 7, 9, and 10. Therefore, claims 1-5, 7, 9, and 10 are obvious over the cited art.
Regarding claim 11, DiMarchi et al. (US 9,062,124 B2) teach pharmaceutical compositions comprising the triple agonist peptides and a pharmaceutically-acceptable carrier (col 58, lines 20-24).
Regarding claims 11 and 17, DiMarchi et al. (US 9,062,124 B2) teach methods of reducing body weight comprising administering the triple agonist peptides to a subject in need thereof (col 62, lines 39-52).
Regarding claim 12, DiMarchi et al. (US 9,062,124 B2) teach methods of reducing body weight comprising administering the triple agonist peptides to a subject suffering from obesity (col 63, lines 7-15).
II. Obviousness of Compounds 6, 10, and 12
Claims 1-5, 7, 9-13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over DiMarchi et al. (US 9,062,124 B2) in view of Just et al. (WO 2015/067716 A1), DiMarchi et al. (WO 2011/143208 A1) and DiMarchi et al. (WO 2012/088116 A2), as applied to the claims above, in further view of Lau et al. (US 2010/0317057 A1).
The instant claims include triagonist peptides Compounds 6 and 10 with the same base amino acid sequence as positions 1-39 of the MT-252, MT-255, MT-277, MT-278, MT-279, MT-280, and MT-323 triagonist peptides of DiMarchi et al. with the following differences:
Instead of the fatty acyl group, the instant claims require a fatty diacid A covalently attached to the peptide by groups B-C (i.e. Chem 10); and
Instead of attachment of this substituent at an additional Lys or Cys amino acid at position 40, the instant claims require that the substituent be attached to the peptide via an epsilon amino group of Lys at position 16 or 17.
In addition, the instant claims include triagonist peptides Compound 12 with one additional difference:
Substitution of aspartic acid with glutamic acid at position 15.
In addition to the changes described in the previous rejection, it would have been obvious to substitute the lipophilic substituent of DiMarchi et al. (US 9,062,124 B2) with Chem 10 taught by Lau et al. Lau et al. teach that the moiety identical to instant Chem 10, like the Chem 6 and Chem 12 taught by Just et al., can be used to acylated the epsilon amino group of a lysine in a therapeutic peptide in order to extend the half-life of the peptide through albumin binding (para. [0078], [0164]-[0166], [0184], Examples 16-17, 24). Doing so would result in Compounds 6, 10, and 12, rendering claims 1-5, 7, 9-13, and 17 obvious over the prior art.
Allowable Subject Matter
Claims 6 and 16 are 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.
Compounds 18, 21-45, and 49-57 and the subgenera represented by claims 6 and 16 are free of the prior art.
The following is a statement of reasons for the indication of allowable subject matter: the closest prior art of DiMarchi et al. (US 9,062,124 B2) teaches GLP-1/GIP/Gcg receptor triple agonists closely related to 18, 21-45, and 49-57 and the subgenera represented by claims 6 and 16. The differences include but are not limited to:
A C18-22 fatty diacid covalently attached to an epsilon-amino group of a lysine at position 16 or 17; and
A histidine at position 3.
Although it may be obvious to modify the triagonists taught by DiMarchi et al. to include a fatty diacid substituent at positions 16, 17, or 21 based on Just et al. (WO 2015/067716 A1), DiMarchi et al. (WO 2011/143208 A1) and DiMarchi et al. (WO 2012/088116 A2), there is no suggestion in the prior art to combine this modification with a glutamine to histidine substitution at position 3. There is no reasonable expectation that doing so would result in the claimed function of a GLP-1/GIP/Gcg receptor triple agonist. For example, DiMarchi et al. (US 9,062,124 B2) teach that substitution of position 3 with an acidic, basic, or hydrophobic amino acid reduces glucagon activity (col 8, lines 49-56; col 20, lines 53-58) and that maintained or enhanced glucagon receptor activity is achieved by a glutamine at position 3 (col 20, lines 59-64). DiMarchi et al. (WO 2012/088116 A2) also teach that substitution of position 3 with an acidic, basic, or hydrophobic amino acid reduces glucagon activity (para. [0224]-[0225]). Just et al. (WO 2015/067716 A1; p. 3, line 24) and DiMarchi et al. (WO 2011/143208 A1; para [0241]-[0242]) also teach that position 3 is Gln (p. 3, line 24). Based on this information, one of ordinary skill in the art would not expect that substituting glutamine with the basic amino acid histidine would conserve glucagon agonist activity. On the contrary, one of ordinary skill in the art would expect that the basic amino acid histidine at position 3 would disrupt glucagon agonist activity, thereby altering the triagonist activity of the peptide. Therefore, Compounds 18, 21-45, and 49-57 and the subgenera represented by claims 6 and 16 are allowable over the prior art. The compounds are enabled for use in methods of reducing body weight, as evidenced by functional potency data presented in Table 2, the terminal half-life data presented in Table 3, body weight reduction data presented in Tables 5 and 7 of the original specification.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
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