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 .
DETAILED ACTION
Election/Restriction
Applicant elected. without traverse, Group I, drawn to a method of enhancing the effectiveness of a beta-arrestin- biased β-blocker, and the species: 1) compound 6 having following structure; 2) carvedilol; 3) heart disease, in the reply filed on 06/30/2026.
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The elected compound species is a compound of Formula I wherein
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Claims 1 and 3-8 read on the elected invention and species.
Claims 10-17 and 19-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 2 and 9 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
The elected compound species, Compound 6 (CAS# 2387694-78-0) was disclosed in prior art and rejected under following 35USC 103. Other non-elected species are withdrawn from further consideration pursuant to 37 CFR 1.142(b). It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be reconsidered. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during reconsideration that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
Status of Claims
Claims 1-17 and 19-21 are pending in the instant application.
Claims 2, 9-17 and 19-21 are withdrawn.
Claims 1 and 3-8 are currently under examination.
Claim Objections
Claims 1 is objected to because of the following informalities:
There is a period following X2 definition in claim 1. Claim 1 also recites “cmpd 6” in parenthesis following definition of X2 group.
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Priority
This instant application 18/707,971 filed May 07, 2024, is a 371 of international patent application No. PCT/US2022/079847, filed on November 15, 2022, which claims the benefit of U.S. provisional application No. 63/280,194, filed on November 17, 2021.
Information Disclosure Statement
The information disclosure statement dated 05/26/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the reference listed in IDS are being considered by the Examiner.
Drawings
The drawings are objected to because Fig. 6, 10 to 16 are blurry and illegible.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1 and 3-8 are rejected under 35 U.S.C. 112(a), because the specification, while be enabling for a method of enhancing efficacy of carvedilol in treating heart failure with specific compound of Formula I (e.g. Compound 6), does not reasonably provide enablement for method genus of enhancing effectiveness of all beta-arrestin-biased β-blocker with any compound of Formula I in treating and/or preventing all heart disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(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.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Instant claims are directed to a method of enhancing the effectiveness of a beta-arrestin-biased β-blocker comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or derivative thereof, and a β-arrestin-biased β-blocker. Instant claimed compound of Formula I comprises vast variety of subgenus/species that have different chemical/physical property and different biological activity, Instant claimed beta-arrestin-biased β-blockers comprise different agents having different chemical structures categorized in different classes and have different biological activity. Thus, instant claim 1 drawn to intended function/result of enhancing effectiveness of a beta-arrestin-biased β-blocker without recitation of any disease/disorder by administering combination genus of compound of Formula I genus and β-arrestin-biased β-blocker genus is extremely broad. Claim 3 recites limitation of treat and/or prevent heart disease in the subject. As disclosed by instant spec [0060], the terms “prevent,” “preventing,” “prevention,” “prophylactic treatment,” and the like refer to reducing the probability of developing a disease, disorder or condition in a subject, who does not have, but is at risk of or susceptible to developing a disease, disorder or condition.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
It is well known in the prior art that treatment for heart disease is highly unpredictable and prevention of heart disease is challenging due to vast variety of factors involved. The effectiveness in treatment of heart disease vary greatly due to a lot factors including compound structures/ physical properties, delivery route, different combinations, etc.. As for using β-arrestin–biased beta-blockers in treating cardiovascular disease (e.g. heart disease), the major challenge is absence of simple criteria to determine when a ligand is intrinsically biased, functionally selective in meaningful settings, or merely selective only in the model system undergoing investigation but completely undifferentiated in more physiologically relevant settings (See DeWire 2011). In particular, instant claims depends on the interaction between compound of Formula I and β-arrestin-biased β-blocker which is highly unpredictable due to different combination.
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient working example to fully support instant claimed method of enhancing the effectiveness of β-arrestin-biased β-blocker with compound of formula I genus in its full scope.
Instant specification discloses working example of compound 6 and a few analog (e.g. A9 ) potentiates the β-arrestin-biased agonism of carvedilol, carvedilol (See Example 1, [0173]). Instant specification dose not disclose working example for other compound of Formula I comprising vast variety of X1, X2, R groups and combination thereof.
Instant specification discloses working example wherein Cmpd-6-induced change in affinity of full agonists (isoproterenol, epinephrine, and norepinephrine), partial agonists (salmeterol, zinterol, procaterol, and clenbuterol) and antagonists (carvedilol, labetalol) to β1ARs (See Fig.16A, [0047]). Instant specification does not disclose what agent are encompassed by instant claimed β-arrestin-biased β-blocker. Instant specification dose not disclose working example wherein compound 6 enhances effectiveness of other β-arrestin-biased β-blocker. Instant specification does not disclose working examples of preventing heart disease. It’ noted instant Cmpd 6 exhibits different activity/ cooperativity in combination with different agent, which illustrates the unpredictability of interaction between vast variety of compound of Formula I and variety of β-blocker. For example, instant specification discloses “no such cooperative effect of cmpd-6 on endocytosis of the receptor was observed in cells treated with the inverse agonist ICI-118551 (FIG. 4C) (See [0173], 0174]). Instant specification disclose that cmpd-6 has absolutely no cooperativity with the antagonist/inverse agonist, carazolol which is similar to carvedilol(See 0181]). As disclosed by instant specification (See [0175]), the cooperativity of cmpd-6 is highly specific to carvedilol amongst a diverse array of known β -blockers tested in this study.
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The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to practice instant claimed method of enhancing the effectiveness of beta-arrestin-biased β-blocker. More working examples would be needed to determine if other compound of Formula I would enhance the effectiveness of beta-arrestin-biased β-blocker for treating variety of disease/disorder. Working examples would be needed to determine the therapeutically effective dose for different combination of compound of Formula I and β-arrestin-biased β-blocker, respectively. The therapeutically effective amount may vary depending on many factors, such as the different combination comprising different compound of Formula I and β-arrestin-biased blocker, the subjects being treated, the disease condition and intended treatment income etc. Furthermore, the specific dosage may vary depending on the compound/combination selected, the dosing regimen to be followed and administration route, etc.
Therefore, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention in full scope.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method of enhancing the effectiveness of beta-arrestin-biased β-blocker in full scope, in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
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.
Claim 1 and its dependent claims 3-8 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 1 recites a method of enhancing the effectiveness of a beta-arrestin-biased β-blocker being administered to a subject, comprising administering to the subject a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or derivative thereof, and a β-arrestin-biased β-blocker such that the effectiveness of the β-arrestin-biased β -blocker is enhanced.
The limitation “prodrug, or derivative” are general terms which refer to vast variety of molecules that have different structures, might be in different recognized chemical classes and have different chemical/physical properties, different pharmaceutical /biological activity, etc. The limitation of prodrug or derivative is not a definite functional group/moiety, thus renders the claim(s) indefinite. An ordinary skilled in the art would not know what compounds/agent are encompassed by prodrug or derivative, thus, the scope of the claim(s) are unascertainable for the patent protection desired.
Claim 1 recites definition of compound of Formula I, and (Cmpd 6). It’s not clear if Cmpd 6 as example or preference is required limitation for the intended scope of claim 1.
The term "enhancing the effectiveness” is a relative term which renders the claim indefinite. It’ not clear what effectiveness of β-arrestin-biased β -blocker in treating what disease/conditions are referred to. The degree of enhancement is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 3-8 are also rejected due to dependency on claim 1.
Claim Rejections - 35 USC § 103
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 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 non-obviousness.
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 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 and 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Lefkowitz et al. (US 2019/0241642 A1, hereafter “Lefkowitz’ 642”, Applicant’s IDS dated 05/26/2026), in view of Wisler et al. ( Proc. Natl. Acad. Sci. 2007, 104 (42) 16657-16662, https://doi.org/10.1073/pnas.0707936104, “A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling”).
Lefkowitz’ 642 discloses compound of Formula I or salt thereof as positive allosteric modulators (PAM) of β2 adrenergic receptor through binding/modulating complex comprising a chimeric G protein coupled receptor (GPCR) comprising a β-arrestin (β arr) protein bound to the C-terminus of the GPCR, and method for treatment of β2 adrenergic receptor mediated disease/disorders (e.g. obstructive airway diseases, etc.)(See abstract, [0013]-[0032], [0136], [0232], Figures 1-23; Examples 1-13; claims 1-14).
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It’s noted Lefkowitz’ 642 compound of Formula I recite the same or similar X1, X2 and R groups that read on instant compound of Formula I.
Lefkowitz’ 642 teaches positive allosteric modulator (PAM) bind to an allosteric binding site and enhance orthosteric ligand affinity wherein PAM ligands may proportionally potentiate activation of G protein or β-arrestin by the orthosteric ligand in cellular assays. “β-arrestin biased positive allosteric modulator” encompasses small molecules that bind to an allosteric binding site which convert a balanced orthosteric agonist into a β-arrestin biased ligand (See [0144]). Lefkowitz’ 642 teaches allosteric modulators (PAMs) of β2 adrenergic receptor display positive cooperativity with orthostatic agonists, thus enhancing their binding to the receptor and ability to stabilize its active state, and exhibit positive cooperativity with G protein and β-arrestin, potentiating their stabilization of high affinity agonist-bound states of the receptor, as well as downstream cAMP production and β-arrestin recruitment to the activated receptor (See [0226]).
Regarding claims 5-7, Lefkowitz’ 642 teaches coadministration of a PAM with a β2 AR agonist may provide enhanced therapeutic effect compared to the therapeutic effect achieved by administration of the β2AR agonist alone(See [0226],[0227]). Lefkowitz’ 642 teaches combination therapy wherein compound of formula I and one or more additional pharmaceutical agents can be administered concurrently or at separately staggered times (e.g., sequentially) (See [0286]).
Regarding claim 8, Lefkowitz’ 642 teaches β2 AR PAMs (See [0015], [0331]), e.g. Cmpd-6 and PAM activity thereof ( See [0331]-[0332]; Examples 6-13) (which reads on instant elected species). Lefkowitz’ 642 teaches Cmpd 6 increases /enhances the binding affinity, stabilizes agonist-induced active conformation, and display positive cooperative with variety of GPCR modulator/ β2ΑR agonist, e.g. isoproterenol, fenoterol, clenbuterol etc. (See Examples 7-13 ).
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Lefkowitz’ 642 collectively teaches the benefit of compound of Formula I (e.g. compound 6) as positive allosteric modulator, e.g. provide enhanced therapeutic effect of β2AR agonist, allow therapeutic administration of β2AR agonists at lower doses, thereby reducing potential toxicity and/or other off-target effects (See [0227]).
Lefkowitz’ 642 is silent about β-arrestin biased β blocker, e.g. carvedilol in instant claim 4 and treating heart disease in claim 3.
Wisler teaches carvedilol, one of three approved treatment for heart failure in U.S, is an unique β-arrestin–biased beta-blocker which antagonizes G protein-mediated signaling while simultaneously stimulating β-arrestin-mediated signaling (See whole article, e.g. abstract; page 16659, right column, last para; page 16660, right column, 2nd para). Wisler teaches carvedilol, a nonsubtype-selective adrenergic receptor antagonist/blocker, stabilizes a receptor conformation which stimulates β-arrestin-mediated signaling through variety of mechanism and provides special efficacy benefits in patients suffering from heart failure compared with other β AR antagonists (See abstract, page 16657, right column). Wisler teaches the unique profile of carvedilol : (i) phosphorylation of the receptor’s cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; (ii) recruitment of β -arrestin to the β 2AR; (iii) receptor internalization; and (iv) β -arrestin -mediated ERK activation: activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant β AR and abolished by β-arrestin2 siRNA (See abstract, Results from page 16657-16658; Discussion). Wisler teaches ligand bias challenges the traditional paradigm of seven transmembrane receptors (7TMR) characterization and β2AR can exist in multiple ‘‘active’’ conformations after ligand binding which could be an effective therapy for the treatment of cardiovascular disease (e.g. heart failure) (See page 16660, left column).
It would have been obvious to one of ordinary skilled in the art before the effective filing date of instant invention to explore Lefkowitz’ 642 compound of formula I (e.g. Compound 6) in combination with other adrenergic receptor modulator for treating cardiovascular disease (e.g. heart disease) based on the combined teachings of Lefkowitz’ 642 and Wisler, together with general knowledge of cardiovascular disease. Lefkowitz’ 642 teaches compound of Formula I (e.g. Compound 6) is positive allosteric modulator of β2 adrenergic receptor associated with positive cooperativity with β-arrestin that enhances efficacy/effectiveness of β2AR agonist. Wisler teaches carvedilol is β-arrestin–biased beta-blocker which activates β-arrestin-mediated signaling and has advantage in treating heart disease compared with other beta-blocker. A skilled artisan would be motivated to explore combination of carvedilol with Compound 6 and reasonably expect the combination of carvedilol with Compound 6 would provide improved/enhanced efficacy compared with carvedilol alone in treating heart disease due to the beneficial/positive allosteric modulation of β2 adrenergic receptor by Compound 6.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art and general knowledge of cardiovascular disease treatment. Please note “enhancing the effectiveness of a beta-arrestin-biased β-blocker” “such that the effectiveness of the β-arrestin-biased β -blocker is enhanced” are considered as intended function/result of administering compound of formula I together with beta-arrestin-biased β-blocker, which does not necessarily further contribute to the structural limitation of instant claimed method . Therefore, the invention as a whole is 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.
Claims 1 and 3-8 are rejected under 35 U.S.C. 103 as being unpatentable over Ahn et al. ( Molecular Pharmacology, 2018, 94:850–861, https://doi.org/10.1124/mol.118.111948, Small-Molecule Positive Allosteric Modulators of the b2-Adrenoceptor Isolated from DNA-Encoded Libraries), in view of Wisler et al. ( Proc. Natl. Acad. Sci. 2007, 104 (42) , 16657-16662, https://doi.org/10.1073/pnas.0707936104, “A unique mechanism of β-blocker action: Carvedilol stimulates β-arrestin signaling”).
Ahn discloses small-molecule positive allosteric modulators of the β2-adrenoceptor that read on instant claimed compound of Formula I, including instant elected species, compound 6(See Fig 1. pg. 852; Table 1).
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Ahn teaches positive allosteric activity of Cmpd-6 for orthosteric ligand binding to the β2AR, e.g. potentiate the binding affinity of agonists for the β2AR, cooperativity with transducers at the β2AR, etc. (See page 854-856, Results ). Ahn teaches Cmpd-6 is cooperative with G protein and β -arrestin1 to stabilize high-affinity, agonist-bound active states of the β2 AR and potentiates downstream cAMP production and receptor recruitment of β -arrestin2 (a.k.a. arrestin3)(See abstract; page 858, right column, Discussion ).
Ahn teaches Cmpd-6 displays differential activity when the orthosteric site of the β2 AR is occupied with variety of agonists, e.g. epinephrine (EPI), fenoterol (FEN), ISO, and clenbuterol (CLEN), etc. (See page 857, right column; page 858, left column).
Ahn is silent about β-arrestin biased β blocker, e.g. carvedilol in instant claim 4 and treating heart disease in claim 3.
The collective teachings of Wisler is elaborated in preceding 103 rejection and applied as before. Wisler teaches carvedilol is β-arrestin–biased beta-blocker which activates β-arrestin-mediated signaling and has advantage in treating heart disease compared with other beta-blocker.
It would have been obvious to one of ordinary skilled in the art before the effective filing date of instant invention to explore Compound 6 taught by Ahn in combination with other adrenergic receptor modulator for treating cardiovascular disease (e.g. heart disease) based on the combined teachings of Ahn and Wisler, together with general knowledge of cardiovascular disease. Ahn teaches Compound 6 and analogs are positive allosteric modulator of β2 adrenergic receptor associated with positive cooperativity with β-arrestin that enhances efficacy/effectiveness of β2AR agonist. Wisler teaches carvedilol is β-arrestin–biased beta-blocker which activates β-arrestin-mediated signaling and has advantage in treating heart disease compared with other beta-blocker. A skilled artisan would be motivated to explore combination of carvedilol with Compound 6 and reasonably expect the combination of carvedilol with Compound 6 would provide improved/enhanced efficacy compared with carvedilol alone in treating heart disease due to the beneficial/positive allosteric modulation of β2 adrenergic receptor by Compound 6.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the teachings of prior art. Therefore, the invention as a whole is 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.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Carr et al. Proc. Natl. Acad. Sci. U.S.A. 113 (28) E4107-E4116, https://doi.org/10.1073/pnas.1606267113 (2016). Carr teaches β-arrestin–biased signaling through the β2 -adrenergic receptor promotes cardiomyocyte contraction (See whole article). Carr teaches carvedilol, currently prescribed nonselective β-blocker, has been classified as a β-arrestin–biased agonist that can inhibit basal signaling from βARs and also stimulate cell survival signaling pathways.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LIYUAN MOU whose telephone number is (571)270-1791. The examiner can normally be reached Mon-Fri 9:00-5:30.
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/L.M./ Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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