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 .
Information Disclosure Statement
The Information Disclosure Statement filed on 01/30/2024, is acknowledged and found to be in compliance with the provisions of 37 CFR § 1.97. Accordingly, the Information Disclosure Statement has been considered.
Application History and Status of Claims
Claims 1-15 were originally presented on 01/30/2024. The preliminary amendments to the claims, also filed on 01/30/2024, were received and entered. Claims 1, 3, 4, 7, 8, 9, 11, and 13 were amended, claims 14 and 15 were canceled, and claims 16-26 were added. Claims 1-13 and 16-26 were pending.
An Election/Restriction requirement was mailed on 03/11/2026, and a response was filed on 05/08/2026. In the response, Applicant filed an amended claim set with amendments to claim 12 only. Those amendments received on 05/08/2026 are acknowledged and entered.
Accordingly, claims 1-13 and 16-26 are pending.
Election/Restriction
As discussed, claims 1-13 and 16-26 were subject to a restriction/election requirement dated 03/11/2026. Applicant’s election “without traverse, the invention of Group I, directed to compounds of formula I-A (regarded as compounds of claim 1), pharmaceutical compositions, and methods of use”, in the response received on 05/08/2026 is acknowledged. The amendments to claim 12 are acknowledged to place the species claimed in that claim within the scope of claim 1.
Three species of the invention were required for election, namely the single compound, the single subject in need thereof, and the single metabolic related disease. Applicant’s election of the following species of the invention, without traverse, is acknowledged. See elections from the response received on 05/08/2026 at 28 and 32:
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Response received on 05/08/2026 at 28 and 32.
The examiner thanks Applicant for providing the variables that recite the elected compound for the various claims.
Applicant states that the elected single compound reads on claims 1-11, 13 and 16-26. The examiner agrees.
Applicant is advised that the Specification at 103-104 appears to provide a chemical name for the elected species compound that is different from the compound drawn directly below the chemical name. See below:
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The examiner will search the structure provided in the election as the elected species, and not the chemical named as the Example 53 compound in the specification.
If the elected species is not anticipated by or obvious over the prior art, the examiner will extend the search and examination to a non-elected species or group of species that falls within the scope of a proper Markush grouping that includes the elected species. A proper Markush grouping that includes the elected species, i.e., the elected single compound Example 53, requires single structural similarity and common use. Accordingly, the proper Markush grouping that includes the elected species requires that the chemicals all have a 2H-chromene moiety bearing 2-8 substitution, with a direct bond at 2 to a phenyl and at 8 to a piperidine, wherein the piperidine is connected by a methylene unit to a benzimidazole (3H-imidazo[4,5-b]pyridine permitted) functionalized with a carboxylic acid moiety.
The effective filing date of Example 53 compound is discussed below.
Priority
The instant application, filed 01/30/2024, is the national stage entry of International Application No. PCT/CN2022/110017, filed 08/03/2022, which claims priority to Chinese Patent Application Nos. CN202110892791.3, filed on 08/04/2021; CN202111322097.4, filed on 11/09/2021; CN202210041958.X, filed on 01/14/2022; and CN202210540040.X, filed on 05/17/2022. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Certified translations of the priority applications have not been received.
In the absence of certified translations of the priority documents, it is not possible to determine which portions of the application are entitled to which priority date. Each priority document discloses new compounds with new structural features and different biological activity.
See, e.g., the instant claim 1 (shown below, left) to understand the variable locations discussed below. Note that in the following discussion, the compound numbers referred to do not necessarily correspond to the Example numbers used in the instant Specification. The numbers used in this discussion are just to count which species of the inventions were disclosed. Also note, that as discussed above in this office action, the claims of the instant application are subject to a restriction and election requirement, and that Applicant has elected the Example 53 compound from the instant Specification (shown to the right, from the Specification at 103-104):
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Claim 1 Structure
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Elected compound structure
CN202110892791.3, filed 08/04/2021
Looking at claim 7 of CN202110892791.3 (pages 8-10), it discloses ~ 63 compounds, or 21 rows of 3 compounds. None of these compounds have W=N. For W=CRm, Rm is only Cl, F, or methyl (no H). All compounds bear L2-B-L3- as L2=bond, B=piperidine, L3=CH2 (i.e., —(CH2)n1—, where n1=1), L4=CH2 (i.e., (CH2)n7—, n7=1), R5=oxetane or a (fluoromethyl)cyclopropane, and the fused bicyclic ring defined by the M1 and M2 variables are benzimidazoles (or variants with N ring heteroatoms at the fused 6 membered ring) substituted at the same position with CO2H. L1 = bond and C is phenyl substituted at 2,4 with halo; occasionally 2-subsitution is methoxy, and 4-substituion is cyano. Examples shown below. The motifs marked by the examiner with a dashed box remain consistent throughout.
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CN202111322097.4, filed 11/09/2021
Looking at claim 9 of CN202111322097.4 (pages 10-15), it discloses ~ 108 compounds, or 36 rows of 3 compounds. Assuming the first 63 compounds are identical to those disclosed in CN202110892791.3, the new features added in compounds 64-108 are the occasional use of B as piperazine, occasional C 2-subsitution as methoxy-D3, occasional use of W=N, and introduction of compounds outside of the scope of claim 1 such as those with the following 6-6 fused bicyclic ring adjacent to B-L1, shown below:
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Several cases where Rm is H, such as the following compounds, were disclosed (note the elected species not present):
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All compounds bear L2-B-L3- as L2=bond, B=piperidine (few piperazine), L3=CH2 (i.e., —(CH2)n1—, where n1=1), L4=CH2 (i.e., (CH2)n7—, n7=1), R5=oxetane or a (fluoromethyl)cyclopropane, and the fused bicyclic ring defined by the M1 and M2 variables are benzimidazoles (or variants with N ring heteroatoms at the fused 6 membered ring) substituted at the same position with CO2H.
CN202210041958.X, filed 01/14/2022
Looking at claim 10 of CN202210041958.X (pages 10-16), it discloses ~ 132 compounds, or 44 rows of 3 compounds. Assuming the first 108 compounds are identical to those disclosed in CN202110892791.3 and CN202111322097.4, the new features added in compounds 109-132 (all on page 16) are the occasional substitution at the carbon adjacent to the chromene oxygen atom with methyl or deuterium, e.g.,
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Occasional use of a 2-pyridine as C appears, such as
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All new compounds bear L2-B-L3- as L2=bond, B=piperidine, L3=CH2 (i.e., —(CH2)n1—, where n=1), L4=CH2 (i.e., (CH2)n7—, n7=1), R5=oxetane or a (fluoromethyl)cyclopropane, and the fused bicyclic ring defined by the M1 and M2 variables are benzimidazoles (or variants with N ring heteroatoms at the fused 6 membered ring) substituted at the same position with CO2H.
The elected species compound is not disclosed, but an isotope-labeled analog is on page 16:
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This analog appears to be designated compound 60 in CN202210041958.X at 85.
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CN202210041958.X at 85.
No data regarding its activity appears to be disclosed. See CN202210041958.X at 85-86 (e.g., the examiner does not see 60 in the table).
CN202210540040.X, filed 05/17/2022
Looking at claim 11 of CN202210540040.X (pages 11-17), it discloses ~ 140 compounds, or 46 rows of 3 compounds with 2 extra compounds. Assuming the first 132 compounds are identical to those disclosed in CN202110892791.3, CN202111322097.4, and CN202210041958.X, the new features added in compounds 133-140 (all on page 17) are occasional changes to the benzimidazoles (or variants with N ring heteroatoms at the fused 6 membered ring) substitution pattern with carboxylic acid bioisosteres. The elected species compound appears to be disclosed on page 17, marked below in a dashed box.
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It appears that this compound is designated compound 64 in CN202210540040.X at 96:
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CN202210540040.X at 96 (appearing to disclose the elected compound).
No data regarding its activity appears to be disclosed. See CN202210540040.X at 101-105 (e.g., the examiner does not see 64 in any of the tables).
PCT/CN2022/110017, filed 08/03/2022
Looking at claim 12 of PCT/CN2022/110017 (i.e., the PCT that this application is a 371 of, which published as WO 2023/011539, pages 116-123), it discloses ~ 158 compounds, or 52 rows of 3 compounds with 2 extra compounds. Assuming the first 140 compounds are identical to those disclosed in CN202110892791.3, CN202111322097.4, CN202210041958.X, and CN202210540040.X, the new features added in compounds 141-158 are occasional changes to the C 2-subsitution with introduction of CO group, e.g.,
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Preliminary in-vitro an in-vivo data for the elected species compound (Example 53) was disclosed on pages 100-101, 103, and 104 (or, in the instant Specification as filed, pages 113, 116, and 117-118.
Initial assessment of effective filing date of the Example 53 compound
As discussed above, it appears that the chemical structure of the elected species compound was disclosed in the CN202210540040.X application, filed 05/17/2022. Method of use data were disclosed in PCT/CN2022/11001, filed 08/03/2022. Thus, the compound may be entitled to a priority date of 05/17/2022, if certified translations of the priority documents are filed. Method of use claims for the Example 53 compound have a filing date of 08/03/2022.
Claim Rejections - 35 USC § 112(b)
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 1-13 and 16-26 Indefinite – Improper Markush Grouping
Claim 1-13 and 16-26 are rejected on the basis that they contain 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.
The Markush grouping of the compounds recited in claim 1 and in the dependent claims 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:
All alternatives are neither all members of the same recognized physical nor chemical class nor the same art-recognized class
MPEP 2117, subsection II.A., explains that a recognized physical or chemical or art-recognized class “is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention”. It gives the example of a fastener a belt, and explains that a buckle, a snap, or a hook and loop structure could each be substituted for each other with the expectation that the same intended result would occur. That expectation arises from a review of the prior art that establishes it was well known that these fasteners could be exchanged to achieve the same purpose. “The equivalence must be disclosed in the prior art or be obvious within the terms of Section 103.” In re Ruff, 256 F.2d 590, 599, 118 USPQ 340, 348 (CCPA 1958).
Here, there is no expectation that arises from a review of the prior art that establishes it was well known that all of the compounds encompassed by claim 1, as well as its dependent claims, could be substituted for each other with the expectation the substituted compound would behave in the same way. This is primarily due to the combined lack of precise definitions for structural features (e.g., aryl, heteroaryl, cycloalkyl, none of which have precise definitions in the specification), limitless optional substitution either explicitly stated in the claim language or permitted by the loose definitions for chemical groups in the specification, and changing distinct core scaffolds, which functionally are defined by the W variable (resulting in a 2H-chromene or a 2H-1,4-benzoxazine) – in combination with the variable linkers to the fused ring system defined by the M variables. See annotated claim 1 to explain these problems:
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Annotated claim 1.
While applicant discloses that select compounds are GLP-1 receptor agonists, there is no expectation from a review of the prior art that the breadth of compounds embraced by the Markush claims would function in this manner. For example, see Jazayeri 20171 at entire document (discussing the GLP-1 receptor, its steric constraints and deep binding pockets), and at Conclusion, page 257 (“The X-ray structure of an agonist-bound full-length GLP-1R unveils the remarkably complex network of interactions between peptide ligand and receptor protein and explains why it has been so difficult to mimic this effect with a small molecule.”). As evidenced from Jazayeri 2017, there is simply no expectation from the prior art that all the alternatives would function as small molecule GLP-1 receptor agonists, due to the massive structural variety permitted by the claims.
All alternatives are neither disclosed in the specification nor known in the art to be functionally equivalent and have a common use
Applicant states that the compounds are “cycloalkene derivative regulator[s]”. See Specification at 1. This is not a class of compounds that is recognized in the art. Applicant suggests that some of the disclosed compounds may function as small molecule GLP-1 receptor agonists, and makes reference to the actives PF-06882961 and PF-07081532, which have been developed to function as small molecule GLP-1 receptor agonists. PF-06882961 (danuglipron) and PF-07081532 (lotiglipron) have the following chemical structures:
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PF-06882961 (danuglipron)
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PF-07081532 (lotiglipron)
Indeed, some of the compounds encompassed by the claims are structurally similar to certain aspects of these known small molecule GLP-1 receptor agonists. However, the claims encompass chemical structures entirely disparate from these known small molecule GLP-1 receptor agonists due to the lack of precise definitions for structural features, limitless optional substitution, and changing distinct core scaffolds, as discussed above.
Further, Applicant provides in-vitro data characterizing only 14 compounds, shown below:
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(52), and
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(53).
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These 14 compounds are structurally similar to PF-07081532 (lotiglipron), and as a result, exhibit nearly the same biological activity. The remaining compounds encompassed by the claims encompass chemical structures that are so disparate from the art recognized small molecule GLP-1 receptor agonists that the Specification itself struggles to define a common use for the compounds. Indeed, it never expressly states that each compound could be substituted for the other, and that when administered to a subject in need, that the same intended result of GLP-1 receptor agonism would occur. Instead, it just states that they are “cycloalkene derivative regulator[s]”, and fails to state a common use for all the alternatives.
All the alternatives do not share both a substantial structural feature and a common use that flows from the substantial structural feature
As shown at the outset of this rejection, all alternatives do not share a substantial structural feature due to the lack of precise definitions for structural features, limitless optional substitution, and changing distinct core scaffolds. As the claims are drafted, the only shared structural feature embraced by all the alternatives is a fused benzene ring and a fused imidazole ring. This structural feature occupies a sliver of the chemical structures encompassed by the claims, and therefore does not represent a common chemical structure that occupies a significant portion of all of the alternatives.
Further, as explained above, common use does not flow from this structural feature. Even though some of the compounds have common use as small molecule GLP-1 receptor agonists, and these compounds also have this fused benzene and imidazole ring structural feature, these identified compounds represent a sliver of the chemical structures embraced by the claims.
Even in cases where the Markush claims have been narrowed, the lack of precise definitions for substituents results in improper Markush groupings where there is again, no shared substantial structural feature and common use that flows. There is simply no “core scaffold” such as coumarin core (see MPEP 2117, subsection IV.A., discussion of In re Harnisch) due to the poorly defined variable substituents which carve out wildly different chemical structures by adding these substituents onto what might be envisioned as a “core scaffold”. Attention is drawn to the MPEP’s discussion of In re Harnisch because Applicant’s compounds that utilize a 2H-chromene by analogy embed a similar “coumarin core”, since coumarins are 2H-chromenes. However, unlike the compounds of In re Harnisch, Applicant’s compounds, when functionalized, no longer retain this core as a substantial structural feature, and therefore lose identity as just 2H-chromenes.
For example, see the instant claim 11, annotated below, note the definitions for R1 and R2, and see definitions in the specification at 28 for alkyl (“The alkyl group can be substituted or substituted… at any available connection point … [and the substitution can be anything].”), at 34 for aryl, which is a permitted substitution for alkyl (“The aryl can be substituted or unsubstituted [and the substitution can be anything].”), and at 35 for alkoxy (“The alkoxy can be optionally substituted or unsubstituted [and the substitution can be anything].”). See annotated claim 11:
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Annotated claim 11.
Accordingly, even for perhaps the narrowest Markush structure, the embedded 2H-chromene “core” represents only a sliver of the chemical structures embraced by the grouping, and there is no evidence established from the prior art, or disclosed in the specification itself, that all alternatives share common use as small molecule GLP-1 receptor agonists. Therefore, common use does not flow from this structural feature for all of the alternatives. Embedding anything as permitted with the above R1 and R2 variables results in wildly different chemicals, and there is no evidence on record that such compounds would have any effect whatsoever on GLP-1 receptors.
Applicant can easily remedy these issues by narrowing the Markush grouping(s) and properly limiting the scope of variable substituents to embrace the disclosed active compounds.
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.
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.
Claims 1-13 and 16-26 Obvious over US’279 in view of US’791
Claims 1-13 and 16-26 are rejected under 35 U.S.C. 103 as being unpatentable over US’279,2 in view of US’791.3
As discussed earlier in this office action, Applicant has elected the Example 53 compound as the single compound for search and examination purposes. Its structure is again shown below. As explained in the election/restriction section, the examiner interprets the election as being to the compound drawn in the specification and provided in the response received on 05/08/2026, and not to the compound named in the specification at 103-104. The elected species compound is an embodiment of all pending claims.
As discussed in the 112(b) section, the Example 53 compound is disclosed in the Specification as a small molecule GLP-1 receptor agonist. It is structurally similar to the known small molecule GLP-1 receptor agonist PF-07081532 (lotiglipron), shown below.4
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US’279 disclosed lotiglipron as the Example 10 compound. See, e.g., US’279 at col. 148 (providing the structure), and at col. 227 (providing an EC50 of 0.96 nM, which is good). The inventors of lotiglipron effectively provide a structure-activity relationship (“SAR”) study around the GLP-1 receptor by tweaking the chemical structures of compounds based upon the general chemical structure disclosed in US’279 at col. 228, claim 1:
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US’279 at col. 228, claim 1.
The inventors of lotiglipron teach that the sp3 hybridized carbon adjacent to the oxygen ring atom accepts a number of substituents, including H. Further, the inventors of lotiglipron teach that the 4-chloro-2-fluorophenyl moiety attached in the S-configuration relative to the 1,3-benzodioxole chiral carbon effectively agonizes the GLP-1 receptor. See, e.g., US’279, Example 5 compound, structure at col. 116, and at col. 227 (providing an EC50 of 1.3 nM, which is also good).
The US’279 Example 5 compound is structurally more similar to the elected species compound than lotiglipron, as shown below. The only structural difference between the two compounds is a C-C double bond, which replaces an oxygen atom of the 1,3-benzodioxole shown in the US’279 Example 5 compound. Otherwise, both compounds do effectively the same thing. I.e., both exhibit the ability to agonize human GLP-1 receptors with good EC50s.
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Example 53 compound (elected species)
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US’279 Example 5 compound
Further, in the field and background of invention sections, US’279 at cols. 1-3 teaches that there was a recognized problem of diabetes as “a major public health concern”, and that the disclosed small molecule “GLP-1R agonists” provide a solution, given that they were “easily-administered”. The background discusses other GLP-1R agonists, such as semaglutide (e.g., WEGOVY or OZEMPIC), which were known to be peptides, that at the time of filing, required administration through s.c. injection to avoid degradation of the peptide in the gastrointestinal tract. See, e.g., WEGOVY Label, dated 06/2021, at 1, which is annexed hereto.
In contrast to these peptides, US’279 teaches that advantageously the disclosed small molecule GLP-1 receptor agonists could instead be prepared in pharmaceutical compositions intended for oral administration (see, e.g., US’279 at col. 27, lines 45-52, teaching tablets). US’279 at cols. 27-30 teaches excipients and carriers for various pharmaceutical compositions.
In summary, US’279 does not appear to expressly teach the slight structural modification depicted in the Example 53 compound.
However, the discovery of small molecule GLP-1 receptor agonists led to a flurry of inventors derivatizing certain structural aspects of the compounds disclosed by Pfizer in US’279. The ISR5 identified many of these patent applications, which generally expand upon the SAR of the GLP-1 receptor disclosed in US’279 by adjusting the various linkers and ring heteroatoms.
The inventors at Gasherbrum Bio, Inc. discovered that by changing the 1,3-benzodioxole of the US’279 Example 5 compound to a 1,4-benzodioxan dramatically increases agonism towards the GLP-1 receptor, dropping the EC50 below 0.2 nM. See, e.g., US’791 compound 130b below, cols. 81 and 189 (also note that the heteroatom placement is consistent with the 3H-imidazolo[4,5-b]pyridine-5-carboxylic acid of the instant example 48 compound, and the EC50s are effectively the same, both being below 0.2 nM):
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US’791 at cols. 81 and 189.
Further, US’791 teaches a SAR about the heteroatom placement in the 1,4-benzodioxan. See, e.g., US’791 compounds 105a, 106a, and 107a below, cols. 65 and 188:
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US’791 at cols. 65 and 188 (left and right, respectively).
One of ordinary skill in the art at the time of filing would interpret the SAR disclosed in US’791 as therefore teaching that only one ring heteroatom was required in the fused 6-membered ring, as well as its preferred placement (see compound 106a, exhibiting the best EC50, 107a, exhibiting an intermediate EC50, and compound 105a, exhibiting the worst EC50). Combining the data disclosed for compounds 105a-107a with the data disclosed for compound 130b (exhibiting a stellar EC50), US’791 teaches the preferred placement of the phenyl ring (shown left below, and compared to the elected species compound, Example 53, right).
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Preferred fused 6-membered ring heteroatom placement and phenyl ring location learned from US’791
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Example 53 compound (elected species)
The above left compound is indeed encompassed by claim 1 of US’791, as well as its 1H-1,3-benzodiazole-6-carboxylic acid variant. Claim 19 teaches its pharmaceutical compositions, and claims 20-21 teaches its use for treating diabetes by oral administration.
The difference between the elected species compound and the preferred structure depicted above that one of ordinary skill in the art at the time of filing would learn from reviewing the SAR of US’279 in view of the SAR of US’791 therefore becomes simply a double bond between two carbons of the fused 6-membered ring, and the heteroatom in the ring fused to the fused imidazole. Alternatively stated, the difference is between a 2H-chromene and a chroman, shown below, and the discussed heteroatom.
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Both US’279 and US’791 teach that the heteroatom about the ring fused to the imidazole is interchangeable and results in stellar agonism of the GLP-1 receptor. That is, the 3H-imidazolo[4,5-b]pyridine-5-carboxylic acid is interchangeable with a 1H-1,3-benzodiazole-6-carboxylic acid variant. One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in incorporating either moiety into a modified GLP-1 receptor according to the SAR of US’279 in view of the SAR of US’791.
Both US’279 and US’791 teach that the GLP-1 receptor prefers a sp3 hybridized carbon adjacent to the oxygen ring atom.
US’279 in particular teaches that the GLP-1 receptor prefers the sp3 hybridized carbon adjacent to the oxygen ring atom to be coplanar with the oxygen atom. The compounds of US’791 lacked that feature due to the chromans and 1,4-benzodioxans utilized in its SARs.
One of ordinary skill in the art at the time of filing would be motivated to exchange the chroman of US’791 to a 2H-chromene in order to prepare more small molecule GLP-1 receptor agonist drugs that advanced the SAR of US’279 in view of US’791, because the 2H-chromene moiety possesses a sp3 hybridized carbon adjacent to the oxygen ring atom that is coplanar with the oxygen atom.
At the relevant time, there was a recognized problem in the art, being diabetes, see supra discussion of US’279 at 1-3, and there was a clear pressure to further optimize the structure of the small molecule GLP-1 receptor agonists based on the drugs disclosed in US’279 for treating diabetes, see, e.g., US’791.
There were a finite number of ways one could optimize the structure of the compounds disclosed in US’279 without losing activity towards the GLP-1 receptor. See, e.g., compound 126a of US’791 at col. 79 (indicating that departing too far from the disclosed structures of US’279 results in a loss of activity towards the receptor, see table entry from compound 126a in US’791 at col. 189 reproduced above a few pages back).
One of ordinary skill in the art at the time of filing would have pursued such a structural modification with a reasonable expectation of success in exchanging the chroman of the preferred fused 6-membered ring heteroatom placement and phenyl ring location learned from US’791 structure shown several pages back with a 2H-chromene because the exchange would result in a coplanar sp3 hybridized carbon adjacent to the oxygen ring atom that was known to effectively result in agonism of the GLP-1 receptor, as discussed for US’279.
Such structural modifications were ordinary and routine to ordinary chemists at the time of filing, as evidenced by US’279 and US’791, each of which effectively teach SAR studies about the GLP-1 receptor. Accordingly, it would only take routine experimentation to synthesize the 2H-chromene derivative and test it in assays against the GLP-1 receptor and in test animals (see, e.g., US’791 at cols. 188 – 192, teaching standard assays and administration to test animals).
One of ordinary skill in the art at the time of filing would have a reasonable expectation of success in administering the compound in a pharmaceutical composition to a subject in need of treatment for diabetes, because the resulting compound would have been reasonably expected to agonize the GLP-1 receptor.
Accordingly, claims 1-13 and 16-26 were obvious at the time of filing.
Claims 1-13 and 16-26 Obvious over US’279 in view of US’791, and in further view of US’193 and Jazayeri 2017
Claims 1-13 and 16-26 are rejected under 35 U.S.C. 103 as being unpatentable over US’279, in view of US’791, and in further view of US’1936 and Jazayeri 2017.7
US’279 and US’791 are relied upon as above, and the rejections of claims 1-13 and 16-26 under 35 U.S.C. 103 as being unpatentable over US’279, in view of US’791, are fully incorporated herein and restated in full.
US’193 is incorporated into the rejections as evidence that ordinary chemists at the time of filing routinely exchanged chromans with 2H-chromenes as part of ordinary drug discovery. See, e.g., US’193 at col. 296, claim 1, shown below.
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US’193 teaches that the chromans and 2H-chromenes it discloses were useful for treating diabetes. See, e.g., US’193 at Abstract
Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
US’193 at Abstract.
While both the compounds and biological targets are different from those disclosed in the instant application, US’193 nevertheless teaches that it was well known at the time of filing to those of ordinary skill in the pharmaceutical arts that chromans and 2H-chromenes were interchangeable, and that the exchange between the two scaffolds normally resulted in similar biological activity. Accordingly, US’193 provides evidence of chromans and 2H-chromenes being utilized as bioisosteres in drug discovery.
Jazayeri 2017 is incorporated into the rejections as evidence that ordinary chemists at the time of filing knew that excessively modifying the chemical structures of known small molecule GLP-1 receptor agonists would lead to no reasonable expectation of success. As discussed in the 112(b) section, Jazayeri 2017 explains that the GLP-1 receptor was difficult to target with small molecules because “[t]he X-ray structure of an agonist-bound full-length GLP-1R unveils the remarkably complex network of interactions between peptide ligand and receptor protein and explains why it has been so difficult to mimic this effect with a small molecule.” Jazayeri 2017 at 257.
Accordingly, ordinary chemists at the time of filing knew that the initial hit disclosed by the inventors at Pfizer in US’279 represented a chemical structure that remarkably and effectively agonized the GLP-1 receptor. Major modifications to the core structures disclosed in US’279 were unlikely to achieve the same result, as evidenced by Jazayeri 2017. Indeed, the inventors in US’791 only achieved success with minor modifications to the structures disclosed in US’279. Therefore, one of ordinary skill in the art at the time of filing, seeking to further optimize the structures taught by the SAR of the GLP-1 receptor by US’279 in view of US’791, would have a reasonable expectation of success in making minor modifications that mimicked the sterics and electronics taught by the disclosed SARs. Jazayeri 2017 provides further evidence motivating ordinary chemists at the time of filing to make the change to a 2H-chromene scaffold, because there was a reasonable expectation that the resulting compound would fit in the same binding location due to mimicking the sterics and electronics taught by the disclosed SAR of US’279 in view of US’791.
Accordingly, claims 1-13 and 16-26 were obvious at the time of filing over US’279, in view of US’791, and in further view of US’193 and Jazayeri 2017.
Conclusion
No claims allowed.
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/C.E.R./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Jazayeri, Ali, et al. "Crystal structure of the GLP-1 receptor bound to a peptide agonist." Nature 546.7657 (2017): 254-258, hereinafter “Jazayeri 2017”.
2 Aspnes; Gary Erik, et al., “GLP-1 Receptor Agonists And Uses Thereof”, U.S. Patent No. US 10934279 B2, published 2021-03-02, Assignee Pfizer Inc., hereinafter “US’279”.
3 Meng; Qinghua, et al., “Heterocyclic GLP-1 Agonists”, U.S. Patent No. US 12552791 B2, published 2026-02-17, priority to 2020-04-29, Assignee Gasherbrum Bio, Inc., hereinafter “US’791”.
4 It is not exactly clear Pfizer publicly linked the pharmaceutical identification number PF-07081532 and/or the name lotiglipron to its chemical structure disclosed in US’279 as of the effective filing date of the instant application. However, as a matter of convenience, it is simple to refer to the compound disclosed as just lotiglipron.
5 A translated copy of the ISR and written opinion is annexed hereto, as they were not previously in the file history.
6 Chen; Helen, et al., “Antidiabetic Bicyclic Compounds”, U.S. Patent No. US 10968193 B2, published 2021-04-06, Merck Sharp & Dohme Corp. Applicant, hereinafter “US’193”.
7 Cited in the 112(b) section.
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