DETAILED ACTION
Examiner acknowledges receipt of the reply filed 5/04/2026, in response to the restriction requirement mailed 3/04/2026.
Claims 1-76 are pending. Claims 1-22, 44-64, 66-74, and 76 are withdrawn from further consideration for the reasons set forth below.
Claims 23-43, 65, and 75 are being examined on the merits in this office 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 .
Priority
The filing receipt dated 4/16/2025 has the following information:
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Election/Restrictions
Applicant’s election of Group 2 (claims 23-43, 59, 62, 65, 68, 71, and 75) without traverse in the reply filed on 5/04/2026 is acknowledged.
Claims 1-22, 44-58, 60, 61, 63, 64, 66, 67, 69, 70, 72-74, and 76 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/4/2026.
Examiner acknowledges election of the following species:
GIP/GLP1 agonist: SEQ ID NO: 13 as in Example 7
Claims 23-43, 65, and 75 read on the elected species. Election was made without traverse in the reply filed on 5/04/2026.
Claims 59, 62, 68, and 71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 5/4/2026.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure relates,” “The disclosure defined by this invention,” “The disclosure describes,” etc. Here, the abstract states “An embodiment of the invention relates to” and “an embodiment relates to”.
Claim Objections
Claims 23-43, 65, and 75 are objected to because of the following informalities:
Claims 23 and 32 recite acronyms that should be written out in full name in the first order of appearance within the claims.
Dependent claims 24-43, 65, and 75 should be amended to recite “The [[A]] method of claim 23, wherein”.
Claims 26 and 27 should be amended to recite “wherein the patient has an HbA1c goal that is”. Claims 28 and 29 should be similarly amended.
Claims 30 and 31 should be amended to recite “wherein the patient [[age]] is at least X years of age”. (Alternatively recite that the patient is X years old).
Claim 43 should be amended to recite “method prevents a stroke”.
Claim 65 should further be amended to recite “salt thereof, is
Claim 75 should be amended to recite “cell membrane guanosine 5'-(gamma-thio) triphosphate-[³⁵S] (GTPγS) binding assay β-Arrestin recruitment assay .
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 26-31 and 75 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 26 and 27 recite the limitation "the patient HbA1c goal”. There is insufficient antecedent basis for this limitation in the claims. To overcome this rejection, the claims should be amended to recite “wherein the patient has an HbA1c goal that is”.
Claims 28 and 29 recite the limitation "the patient HbA1c”. There is insufficient antecedent basis for this limitation in the claims. To overcome this rejection, the claims should be amended to recite “wherein the patient has an HbA1c that is”.
Claims 30 and 31 recite the limitation "the patient age”. There is insufficient antecedent basis for this limitation in the claim. To overcome this rejection, the claims should be amended to recite “wherein the patient [[age]] is at least X years of age”.
Claim 75 recites the limitation " the GLP-1R HEK293 Cell Membrane Guanosine…” and ”the GLP-CHO Cell ß-Arrestin. Recruitment Assay”. There is insufficient antecedent basis for this limitation in the claim.
The metes and bounds of claim 75 are deemed to be indefinite. Claim 75 recites:
A method as claimed by Claim 23 wherein [the ?] GIP/GLP1 agonist is a compound showing partial agonism in the GLP-1R HEK293 Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[³⁵S] (GTPγS) Binding Assay is co- administered with a compound of a compound showing 35% or less in the GLP-CHO Cell ß-Arrestin. Recruitment Assay.
The claim scope is unclear. For instance, what is a compound of a compound? It is unclear as to what the term “35% or less” specifically relates to.
Additionally, while features of an apparatus may be recited either structurally or functionally, claims directed to an apparatus (or composition) must be distinguished from the prior art in terms of structure rather than function. In re Schreiber, 128 F.3d 1473, 1477-78, 44 USPQ2d 1429, 1431-32 (Fed. Cir. 1997).
Claim clarification is required.
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 23-43, 59, 62, 65, 68, 71, and 75 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 treating high blood pressure in patients with type 2 diabetes, does not reasonably provide enablement for treating all patient populations much less preventing a hypertensive crisis or a stroke. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
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." These factors include, but are not limited to:
(1) The breadth of the claims; (2) The nature of the invention; (3) The state of the prior art; (4) The level of one of ordinary skill; (5) The level of predictability in the art; (6) The amount of direction provided by the inventor; (7) The existence of working examples; and (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Regarding factors (2) The nature of the invention and (1) The breadth of the claims: Claim 42 is drawn to a method of treating high blood pressure in a patient in need thereof, comprising administering an effective amount of GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method prevents hypertensive crisis. Claim 43 is drawn to a method of treating high blood pressure in a patient in need thereof, comprising administering an effective amount of GIP/GLP1 agonist, or a pharmaceutically acceptable salt thereof, to the patient once weekly, wherein the method prevents stroke.
The specification states at p 6: “hypertensive crisis” means blood pressure is dangerously high and may threaten patient organs or life. Hypertensive crisis is typically blood pressure that is at least 180/120. High blood pressure is generally 130/80 systolic/diastolic pressure.
(3) The state of the prior art:
Goud et al (Curr Hypertens Rep 18:16 (2016)) teach that blood pressure BP-lowering effects have been observed in mouse models of hypertension with a variety of GLP-1 agonists (abstract, Tables 1-2, Fig 1; pp. 2-4).
Lovshin et al (Can J Diabetes 38:364-371 (2014)) teach that GLP1 agonists have been associated with systolic blood pressure reduction (abstract). As hypertension is an independent risk factor for premature death in patients with type 2 diabetes, potential favourable extrapancreatic actions, particularly within the heart, blood vessels and kidney, for this drug class are of considerable clinical interest. Id. See also pp. 366-370; Table 2.
Heimbürger et al, “Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular Disease,” Peptides 125:170174 (online Nov 2019) discloses blood pressure-lowering effects of GIP (e.g., abstract, pp 3-6).
Shelton (U.S. 2016/280754) discloses dual GIP/GLP-1 agonists that can be used to treat elevated blood pressure or hypertension (e.g., paras [0200], [0205], [0306]-[0310], claims 28, 33). Shelton discloses that the GIP/GLP-1 agonists can be administered by injection (e.g., paras [0314], [0319], Ex 3-5, claim 23).
Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) - cited in IDS filed 8/15/2023) teach the results of a clinical trial assessing the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes that received once-weekly subcutaneous tirzepatide (also known as LY3298176; a dual GIP/GLP-1 agonist) (abstract, pp 939-940).
(4) The relative skill of those in the art:
MPEP 2141.03 states (in part)” A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) (disagreeing with the examiner’s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering). In the instant case, the skill in the art high with respect to physicians and scientists. The level of skill in the art (physicians and scientists) would be high.
(5) The predictability or unpredictability of the art: The invention is directed toward the treatment of disease 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 is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
It is noted that pharmaceutical and biological art is generally unpredictable, requiring each embodiment to be individually assessed for physiological activity. Given this fact, historically the development of new drugs has been difficult and time-consuming. Adding to the unpredictability is that many treatment options may show promise in animal models, but may fail to show therapeutic improvement in clinical trials. There is no absolute predictability, even in view of the high level of skill in the art.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
Example 1 discloses a prophetic clinical trial of a GIP/GLP1 agonist in treating diabetes, including patients considered to be refractory to type 2 diabetes oral treatment. Example 2 discloses a prophetic clinical trial of a GIP/GLP1 agonist in treating patients considered to be refractory to type 2 diabetes oral treatment. Example 3 discloses a clinical trial of a GIP/GLP1 agonist in treating type 2 diabetic with glycemic control not well controlled on diet/exercise and metformin. The specific dual agonist used in the study was not identified. Table 5 indicates that systolic and diastolic blood pressure decreased at the end of the study compared to placebo. Examples 4-10 disclose SEQ ID NOs:10-14, 21 and 22, respectively. Examples 11-15 disclose SEQ ID NOs:23-26 and 41, respectively. Examples 16-19 disclose SEQ ID NOs:17-19, respectively. The specification further discloses binding assays of GIP and GLP-1 receptors (Tables 6 and 8).
The patient population administered the GIP/GLP1 agonist [compound not expressly identified] was limited to type 2 diabetics with high blood pressure Ex 3). There is no evidence of “preventing" hypertensive crisis or a stroke.
It is further noted that in order to prevent a disorder, the patient population at risk for developing a disorder must be identified, and an effective amount and dosing regimen must be administered.
(8) The quantity of experimentation necessary: Owing to factors 1-7 the quantity is expected to be high.
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 justified here.
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.
Claim(s) 23-26, 28, 30, 31, 33, 34, and 37-43 is/are rejected under 35 U.S.C. 103 as being unpatentable Shelton (U.S. 2016/280754), and further in view of Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) - cited in IDS filed 8/15/2023) and Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) – supplemental information, 14 pages ).
Shelton discloses dual GIP/GLP-1 agonists that can be used to treat elevated blood pressure or hypertension (e.g., paras [0200], [0205], [0306]-[0310], claims 28, 33). Shelton discloses that the GIP/GLP-1 agonists can be administered by injection (e.g., paras [0314], [0319], Ex 3-5, claim 23). Shelton taught the correlation between cardiovascular diseases and diabetes/obesity (e.g., paras [0002], [0199], [0307]-[0308], [0331]). A therapeutically effective amount of a compound will depend, e.g., on the route of administration, the type of mammal being treated, and the physical characteristics of the specific mammal under consideration. These factors and their relationship to determining this amount are well known to skilled practitioners in the medical arts. This amount and the method of administration can be tailored to achieve optimal efficacy, and may depend on such factors as weight, diet, concurrent medication and other factors, well known to those skilled in the medical arts. The dosage sizes and dosing regimen most appropriate for human use may be guided by the results obtained by the present invention, and may be confirmed in properly designed clinical trials. An effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Numerous factors may be taken into consideration by a clinician when determining an optimal dosage for a given subject (e.g., paras [0314]-[0316]).
Although Shelton teach subcutaneous injection of a GIP/GLP-1 agonist to treat elevated blood pressure or hypertension, the reference doesn’t explicitly teach a dosing regimen of once weekly administration.
Frias et al teach the results of a clinical trial assessing the efficacy and tolerability of tirzepatide treatment using three different dose-escalation regimens in patients with type 2 diabetes that received once-weekly subcutaneous tirzepatide (also known as LY3298176; a dual GIP/GLP-1 agonist) (abstract, pp 939-940). Frias taught that tirzepatide treatment with 12 and 15 mg doses resulted in statistically and clinically significant reductions in HbA1c and body weight that were comparable with those observed in the larger primary phase 2b study in a similar patient population with type 2 diabetes (abstract, p 945).
It would have been obvious to one of ordinary skill in the art to administer a GIP/GLP1 agonist to a treat high blood pressure or hypertension, as taught by Shelton et al. Shelton further taught routes of administration (subcutaneous injection) and that an effective amount could be determined by the skilled artisan. The skilled artisan would have recognized that tirzepatide (a GIP/GLP1 agonist) was effective as a once weekly injection in type 2 diabetic patients, as taught by Frias. The skilled artisan would have had a reasonable expectation of success in treating type 2 diabetic/obese patients with high blood pressure with a weekly injection of tirzepatide because this is the patient population that both Shelton and Frias sought to treat. Shelton taught diseases or conditions caused or characterized by excess body weight included obesity, diabetes, and hypertension (e.g., [0199]-[0205], [0331], claims 27, 28, and 33).
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650.
Accordingly, clam 23 is rendered obvious.
Regarding claim 24, the study included patients diagnosed with type 2 diabetes for more than 9.1 years (Frias at p. 941, see also Table 1). Regarding claim 25, patients included those with type 2 diabetes inadequately controlled with a stable dose of metformin [reads on refractory type 2 diabetes, not controlled by oral medication, e.g. metformin] (Frias at pp 939-940). Regarding claim 26, the HbA1c goal was less than 7%. Table 1 of Frias indicate baseline HbA1c% values of 8.4 ± 0.90 (TZP12 mg), 8.5 ± 1.17 (TZP 15 mg-1), and 8.4 ± 1.12 (TZP 15 mg-2). After 12 weeks, the change from baseline was -1.7 (TZP12 mg), -2.0 (TZP 15 mg-1), and -1.8 (TZP 15 mg-2). Thus, the final HbA1c % values were 6.7% (TZP12 mg; e.g., 8.4 % baseline – 1.7 change from baseline = 6.7%), 6.5% (TZP 15 mg-1), and 6.6% (TZP 15 mg-2) (Frias at abstract, Fig S1). Regarding claim 28, the study included patients with HbA1c greater than 10%, e.g., 10.5% (Frias at p. 9439).
Regarding claim 30, patients were at least 46 years of age (mean age in the study was 57.4 years) (Frias at abstract, p 941). Regarding claim 31, the study included patients at least 61±7.56 years of age (Frias Table 1). Regarding claim 33, patients were treated with a stable dose of metformin (e.g. Frias at p. 940, Table 1). Regarding claim 34, patients were treated not administered a basal insulin [lack of teaching is construed as reading on the claim] (e.g. Frias).
Regarding claim 37, the patient can be obese (e.g., Shelton paras [0008], [0198], [0205], [0229], [0302]-[0309], Example 5, claims 26, 33). Regarding claim 38, the patient can be overweight which is distinguishable from obese (Shelton para [0229]). Further regarding claims 37 and 38, patients in the study included obese and non-obese patients (BM between 23-45 kg/m2) (Frias at p 939). Regarding claim 39, low HDL cholesterol is a cardiovascular risk factor in diabetic and/or obese patients (e.g., Shelton at paras [0002], [0306]-[0310]). Regarding claim 40, Frias et al teach that patients included waist circumferences (cm) of 107.7 ± 12.23, 107.0 ± 12.65, and 105.1 ± 12.19 (Table 1). Frias teaches the patient population representing patients with at least two cardiovascular risk factors, those being an older mean age, higher BMI, longer history of diabetes. The average age, HbA1c, BMI and duration of diagnosed type 2 diabetes were 57.4 years, 8.4% (67.8 mmol/mol), 31.9 kg/m2 [obese] and 9.1 years, respectively p. 941). It is further noted that Shelton taught the correlation between obesity/diabetes and hypertension. Regarding claims 41-43, Shelton teaches that “treatment” is an intervention performed with the intention of preventing the development or altering the pathology of a disorder. Accordingly, “treatment” refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those already with the disorder as well as those in which the disorder is to be prevented. By treatment is meant inhibiting or reducing an increase in pathology or symptoms (Shelton at para [0318]). Diseases to be treated include atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke; and elevated blood pressure, hypertension (e.g. Shelton at paras [0200], [0309]-[0310], [00331], claims 25, 28).
Claims 23-26, 28, 30, 31, 33, 34, and 37-43 are rendered obvious by the teachings of Shelton and Frias.
Claim(s) 23-26, 28, 30, 31, 33, 34, 37-43, 65, and 75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shelton (U.S. 2016/280754), and further in view of Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) - cited in IDS filed 8/15/2023) and Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) – supplemental information, 14 pages), as applied to claims 23-26, 28, 30, 31, 33, 34, and 37-43 above, and further in view of Abraham et al (WO2020023386 – publ 1/30/2020; cited in IDS filed 8/15/2023).
The teachings of Shelton and Frias are set forth above. Although the references teach dual GIP/GLP-1 agonists and treatment of elevated blood pressure and hypertension, the references do not explicitly teach the elected species SEQ ID NO:13.
Abraham et al disclose GIP/GLP1 agonists, including SEQ ID NO:13 (Example 4). SEQ ID NO:13 of Abraham et al has 100% identity with instant SEQ ID NO:13. The GIP/GLP1 agonists of Abraham et al can be used to treat obesity, obesity related disorders, and type 2 diabetes (e.g., abstract, pp. 1, 17-18, 20).
It would have been obvious to one of ordinary skill in the art to substitute tirzepatide of Frias with SEQ ID NO:13 of Abraham in a method of treating high blood pressure. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting because tirzepatide and SEQ ID NO:13 are both explicitly taught as being useful as GIP/GLP1 agonists. Shelton also taught GIP/GLP1 agonists. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
The skilled artisan would further have had a reasonable expectation of success in treating type 2 diabetic/obese patients with high blood pressure with a weekly injection of the GIP/GLP1 agonist of SEQ ID NO:13 because this is the patient population that Abraham, Shelton, and Frias sought to treat. Shelton and Abraham taught diseases or conditions caused or characterized by excess body weight included obesity, diabetes, and hypertension (e.g., [0199]-[0205], [0331], claims 27, 28, and 33).
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650.
Accordingly, claim 65 is rendered obvious.
Regarding claim 75, Abraham et al taught compounds of formula I (e.g., including instant SEQ ID NO:13) is a partial agonist on the GLP-1R as demonstrated by a Cell Membrane Guanosine 5'-(gamma-thio) Triphosphate-[35S] (GTPyS) Binding Assay. The compound is administered with a compound showing 35% or less in the GLP-CHO Cell b-Arrestin.Recruitment Assay (e.g., pp. 32, 124-132, claims 69, and 95-100).
Claims 23-26, 28, 30, 31, 33, 34, 37-43, 65, and 75 are rendered obvious by the teachings of Shelton, Frias, and Abraham.
Claim(s) 23-43, 65, and 75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shelton (U.S. 2016/280754), Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) - cited in IDS filed 8/15/2023), Frias et al (Diabetes Obes Metab 22: 938-946 (epublished 02/11/2020) – supplemental information, 14 pages) and Abraham et al (WO2020023386 – publ 1/30/2020; cited in IDS filed 8/15/2023), as applied to claims 23-26, 28, 30, 31, 33, 34, 37-43, 65, and 75 above, and further in view of Alsina-Fernandez et al (WO2020023388 – publ 1/30/2020; cited in IDS filed 8/15/2023), Sherwani et al (Biomark Insights 11:95-104 (2016)), Brown et al (Obesity Rev 20:816-828 (2019)), and Clinical trial NCT03954834, “A Study of Tirzepatide (LY3298176) in Participants With Type 2 Diabetes Not Controlled With Diet and Exercise Alone (SURPASS-1),” dated 02/03/2020, accessed at URL clinicaltrials.gov/study/NCT03954834?cond=NCT03954834&viewType=Card&rank=1&tab=history&a=20#version-content-panel on 9/2/2026, hereinafter referred to as “the ‘834 Clinical Trial”.
The teachings of Shelton, Frias, and Abraham et al are set forth above. Shelton, Frias, and Abraham do not expressly teach the limitations of instant claims 27, 29, 32, 35, and 36.
Alsina-Fernandez et al teach methods of treating diabetes and obesity comprising a dosing regimen of a GIP:GLP-1 dual agonist peptide (abstract). “HbA1c” refers to glycated hemoglobin levels, which develop when hemoglobin joins with glucose in the blood. HbA1c levels are a commonly used measure of glycemic control in patients with diabetes, with decreased HbA1c levels generally indicating improved glycemic control (p. 49, l. 30-p. 50, l. 1).
Sherwani et al teach that diabetes is a global endemic with rapidly increasing prevalence in both developing and developed countries. The American Diabetes Association has recommended glycated hemoglobin (HbA1c) as a possible substitute to fasting blood glucose for diagnosis of diabetes. HbA1c is an important indicator of long-term glycemic control with the ability to reflect the cumulative glycemic history of the preceding two to three months. HbA1c not only provides a reliable measure of chronic hyperglycemia but also correlates well with the risk of long-term diabetes complications. Elevated HbA1c has also been regarded as an independent risk factor for coronary heart disease and stroke in subjects with or without diabetes (abstract). Diabetes-related complications are directly proportional to the levels of HbA1c – the increase in the HbA1c levels also increases the risk of such complications (p. 101). Table 1 indicates that an HbA1c of 11% correlates with less controlled diabetes. A lower HbA1c (such at 5.6% or less) correlates with healthy/normal levels (p. 101, left col; Table 1).
Brown et al teach sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) and glucagonlike peptide receptor agonists (GLP‐1 RAs), concomitantly target weight loss and glycemic control (abstract). Brown et al teach a clinical trial (DURATION‐8, a 28‐week randomized controlled trial) which considered the efficacy and safety of combination therapy with dapagliflozin and Exenatide QW in T2DM, inadequately controlled by metformin. There were significantly greater reductions in absolute weight change with exenatide plus dapagliflozin (−3.41 kg) versus exenatide (−1.54 kg) or dapagliflozin (−2.19 kg) alone. The AWARD‐10 study demonstrated greater weight loss with the sequential addition of dulaglutide 1.5 mg to patients treated with SGLT2i (with or without metformin) (pp. 823-824).
The ‘834 Clinical Trial discloses weekly administration of the GIP/GLP-1 dual agonist tirzepatide over 47 weeks.
Regarding claim 27, the skilled artisan would have recognized that Alsina-Fernandez and Sherwani taught HbA1c values (normal/healthy) that a patient with type 2 diabetes would seek to attain during treatment. The patient glycemic goal is less than about 5.7% (Alsina-Fernandez at p. 50, l. 32 – p 51 l. 4). Sherwani et al teach that a lower HbA1c (such at 5.6% or less) correlates with healthy/normal levels (p. 101, left col; Table 1). Accordingly, claim 27 is rendered obvious.
Regarding claim 29, Sherwani teaches that patients with HbA1c levels of 6.4% or higher have diabetes (p. 101, left col; Table 1). Diabetes-related complications are directly proportional to the levels of HbA1c – the increase in the HbA1c levels also increases the risk of such complications (p. 101). Table 1 indicates that an HbA1c of 11% correlates with less controlled diabetes. The skilled artisan would have recognized that a patient with a HbA1c over 11% would benefit from treatment with a GIP/GLP1 agonist. As taught by Frias, GIP/GLP-1 dual agonist treatment resulted in clinically significant reductions in HbA1c. Shelton, Frias, and Alsina-Fernandez taught treatment of diabetes comprising a GIP/GLP-1 dual agonist. Accordingly, claim 29 is rendered obvious.
Regarding claims 32 and 35, the skilled artisan would have recognized from Brown that sodium‐glucose co‐transporter 2 inhibitors (SGLT2i) are used to treat type 2 diabetes and obesity (abstract). Brown further taught that a combination of a GLP1 agonist and SGLT2 inhibitor in type 2 diabetic patients inadequately controlled by metformin resulted in greater weight loss than either drug alone. It would have been obvious to the skilled artisan to administer a dual GIP/GLP1 agonist to a patient that failed on metformin/SGLT2 inhibitor. The skilled artisan would have had a reasonable expectation of success because Brown disclosed advantages of a GLP1 agonist. The skilled artisan would have recognized that dual GIP/GLP1 agonist targeting two incretin receptors would be more beneficial than a GLP1 agonist alone.
The U.S. Federal Circuit has explicitly stated that in order to make a prima facie case of obviousness, the suggestion and motivation to combine the references need not be explicitly stated in the text of the references. In DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 80 USPQ2d 1641 (Fed. Cir. 2006), the Court writes, “the suggestion test is not a rigid categorical rule. The motivation need not be found in the references sought to be combined, but may be found in any number of sources, including common knowledge, the prior art as a whole, or the nature of the problem itself. In re Dembiczak, 175 F.3d 994, 999 [50 USPQ2d 1614] (Fed. Cir. 1999). As we explained in Motorola, Inc. v. Interdigital Tech. Corp., 121 F.3d 1461, 1472 [43 USPQ2d 1481] (Fed. Cir. 1997), ‘there is no requirement that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.’” See Dystar at 1645. “Our suggestion test is in actuality quite flexible and not only permits, but requires, consideration of common knowledge and common sense.” See Dystar at 1650. Accordingly, claims 32 and 35 are rendered obvious.
Regarding claim 36, Shelton teaches that an effective dosage and treatment protocol may be determined by conventional means, starting with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well (e.g., paras [0315]-[0316]). Frias teaches a 12 week clinical trial of a GIP/GLP-1 dual agonist. Alsina-Fernandez discloses a 26 week phase II clinical trial of a GIP/GLP-1 dual agonist. The ‘834 Clinical Trial discloses weekly administration of the GIP/GLP-1 dual agonist tirzepatide over 47 weeks.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the length/duration of treatment. The rationale comes from MPEP 2144.05, stating that a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America V. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)". In this case, Frias, Alsina-Fernandez, and the ‘834 Clinical Trial disclose treatment times with a GIPP/GLP1 agonist of 12, 24, and 47 weeks. Shelton further teaches that the skilled artisan can assess/determine effective dosage amounts and treatment regimens. There is no indication from the specification that treatment duration is a critical element that precludes optimization through routine experimentation. The skilled artisan would have had a reasonable expectation of success because the prior art disclose various treatment durations. The invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. Accordingly, claim 36- treatment of at least 40 weeks- is rendered obvious.
Claims 23-43, 65, and 75 are rendered obvious by the teachings of the cited references.
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 23-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-117 of copending Application No. 18/546477 (hereinafter referred to as “the ‘477 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 23, claim 26 of the ‘477 application recites that an effective amount of tirzepatide (reads on GIP/GLP1 agonist) can be administered once weekly to treat high blood pressure in a patient.
Regarding claim 24, the patient has type 2 diabetes for at least 8 years (claim 27). Regarding claim 25, the patient has refractory type 2 diabetes (claim 28). Regarding claims 26-29, the patient HbA1c less than 7% (claim 29); equal to or less than 5.7% (claim 30); greater than 10% (claim 31); greater than 11% (claim 32).
Regarding claims 30 and 31, the patient is at least 46 years old (claim 33); at least 60 years old (claim 34)
Regarding claims 32-35, the patient takes a SGLTR inhibitor (claim 35); taking metformin (claim 36); not administered basal insulin (claim 37); fails to reach Hb1ac goal while taking metformin and SGLTR inhibitor (claim 38).
Regarding claim 36, dual agonist treatment for at least 40 weeks (claim 39).
Regarding claims 37-40, patient has comorbid obesity (claim 40); patient is non-obese (claim 41); patient has low HDL-C (claim 45); patient has at least 2 cardiovascular risk factors (claim 46).
Regarding claims 42 and 43, the method prevents hypertensive crisis (claim 48); prevent stroke (claim 49).
Claims 23-43 and 65 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 14-117 of copending Application No. 18/546477 (hereinafter referred to as “the ‘477 application” in view of Abraham et al (WO2020023386 – publ 1/30/2020; cited in IDS filed 8/15/2023).
This is a provisional nonstatutory double patenting rejection.
The claims of the ‘477 application are disclosed above. Although the claims disclose administering tirzepatide (reads on GIP/GLP1 agonist) once weekly to treat high blood pressure in a patient, the claims do not recite the elected species SEQ ID NO:13.
Abraham et al discloses GIP/GLP1 agonist, including SEQ ID NO:13 (Example 4). SEQ ID NO:13 of Abraham et al has 100% identity with instant SEQ ID NO:13. It would have been obvious to one of ordinary skill in the art to substitute tirzepatide of the ‘477 application claims with SEQ ID NO:13 of Abraham in a method of treating high blood pressure.
A person of ordinary skill in the art would have had a reasonable expectation of success in substituting because tirzepatide and SEQ ID NO:13 are both explicitly taught as being useful as GIP/GLP1 agonists. Therefore, these compositions are functional equivalents in the art, and substituting one for the other would have been obvious at the time of the invention. “When a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious.” See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007) at 1395-1396, quoting Sakraida v. AG Pro, Inc., 425 U.S. 273 (1976) and In re Fout, 675 F.2d 297, 301 (CCPA 1982) (“Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious”).
Accordingly, claim 65 is rendered obvious.
Conclusion
No claims are allowed.
Claims 1-76 are pending. Claims 1-22, 44-64, 66-74, and 76 are withdrawn.
Claims 23-43, 65, and 75 are rejected.
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/KRISTINA M HELLMAN/Examiner, Art Unit 1654
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