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 (IDS) submitted on 12/26/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure is being considered by the examiner.
Claim Objections
Claim 2 is objected to because of the following informalities: “gestation diabetes” should be “gestational diabetes”.
Claim 9 is objected to because of the following informalities: “treating an obesity in a subject” should be “treating obesity in a subject”.
Claim 17 is objected to because of the following informalities: “…for reducing or inhibiting reduce triglyceride-rich-lipoproteins…” should be “…for reducing or inhibiting triglyceride-rich-lipoproteins…”.
Claim 18 is objected to because of the following informalities: “..gestation diabetes, is obesity…” should be “gestational diabetes, obesity…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 2, 4-9,11-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Scope of the claimed genus:
Claims 1, 2, 4-9 are drawn to methods of treating a metabolic disease or obesity by administering an effective amount of a GHRH antagonist or pharmaceutical composition comprising a GHRH antagonist to reduce triglyceride-rich-lipoproteins (TRL). Claims 11-18 are drawn to a method of reducing TRL by administering an effective amount of a GHRH antagonist or pharmaceutical composition. Accordingly, the claims encompass all GHRH antagonists.
State of the relevant prior art:
It was known in the art at the time of filing that D-Arg at position 2 of GHRH analogs is essential for antagonistic activity (Zarandi, pg. 12301, right side, second paragraph; see instant PTO-892). A broad genus of GHRH antagonists are known in the art.
However, the reduction in TRL is not an established effect of all GHRH antagonists known in the art. Central and periphery GHRH receptors have different binding affinities for GHRH analogues, different expression levels, and different functions ( Yu et al. pg.466; Table 1; pg. 468, left side, second paragraph; see instant PTO-892). While the primary function of GHRH in the pituitary gland is to produce growth hormone (GH), GHRH receptors in the periphery can have different effects that are not yet fully understood. There is one GHRH antagonist, MIA-602, known in the art to reduce TRL in type I diabetes through periphery receptors; however, the reduction in TRL was not due to the reduction in growth hormone (GH), but rather through normalization of GLP-1 signaling (Romero, pg. 1899, left side, first paragraph; see instant PTO-892). In other words, the desired effect (i.e. reduction in TRL) was not achieved by modulating the primary function of GHRH receptors (i.e. GH production) but rather a separate downstream mechanism (i.e. GLP-1 signaling) that is not well understood in the art (Romero, pg. 1899, right side, third paragraph).
Due to the differences in receptor expression and function throughout the body and the lack of sufficient understand of precisely how the MIA-602 lowered TRL levels, one of ordinary skill in the art would not immediately envisage the claimed function, namely reduced TRL levels, from every GHRH antagonist.
Description of representative species in the specification:
Because the relationship between GHRH antagonistic activity and a TRL reduction effect is not fully established in the art, the specification needs to provide a representative number of species in order to demonstrate possession of the entire genus.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The specification discloses a GHRH antagonists MIA-602 (Example 4) and AVR-352 (Example 10) that successfully reduced triglyceride levels in vivo. It also teaches several other GHRH antagonists (pg.15-16) which were not tested in vivo but contain the D-Arg at position two. The specification does not elucidate why the exemplary GHRH antagonists (pg.15-16) would be expected to perform the recited function, namely reduce triglyceride levels, without confirmation by testing in vivo. Given the breadth of genus and the lack of the support from the state of the art, the disclosed species are not sufficient to constitute the genus.
Identifying characteristics and structure/function correlation:
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the TRL reduction activity. As discussed above, the GHRH antagonist species disclosed in the specification have the required structural element of the D-Arg at position two in the sequence; however, as discussed above, it does not necessarily follow that a GHRH antagonist would achieve the recited function. The specification does not identify any correlation between structure required to achieve the recited function.
Accordingly, in view of the instant disclosure, one of ordinary skill in the art would be unable to envisage the necessary structure of the full genus of GHRH antagonists comprising the effect of TRL reduction.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-4, 7-12, and 16-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Romero-Lucas US20170202907A1 (hereafter Romero-Lucas I), as evidenced by Gabriel, The use of subcutaneous infusion in medication administration, 2013, Br J Nurse, abstract (see instant PTO-892).
Regarding Claims 1-3 and 17-19, Romero-Lucas I teaches treating a metabolic disease, wherein the disease is type I diabetes, by administering an effective amount of growth hormone-releasing hormone (GHRH) antagonist, wherein the antagonist is MIA-602 [0006], to a subject to reduce triglyceride-rich-lipoproteins (TRL). As defined by instant claim 3, administration of MIA-602 of Romero-Lucas I will naturally decrease TRL levels. Regarding claims 4 and 11, Romero-Lucas I teaches that the GHRH antagonist is administered subcutaneously ([0013], [0039]); as evidenced by Gabriel, subcutaneous administration is a type of parenteral administration (abstract). Regarding claims 5-6, Romero-Lucas I teaches that MIA-602 was administered three times a week ([0025]), which would require that MIA-602 inevitably be administered sometime before a meal. Regarding claim 7, Romero-Lucas I teaches that the GHRH antagonist is administered intermittently (i.e. three times a week for 14 weeks) ([0025]). As defined by the specification [00042], the patient population for treating obesity is the same as that of claim 1 (i.e. population with a metabolic disease), because type-2 diabetes is a metabolic disease characterized by central obesity. Therefore, Romero-Lucas I also reads on claims 9-11 because it treats the same patient population with the same active method steps described previously. Furthermore, Romero-Lucas I reads on claim 12 because everyone is at risk for obesity. Regarding claims 8 and 16, Romero-Lucas teaches inhibiting GHRH as a therapeutic approach for patients ([0024]) who are human ([0017]).
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 following rejection of claims 5 and 6 is made in case the claims require that the subject is administered MIA-602 right before a meal.
Claim(s) 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romero-Lucas I, as applied to claim 1 above, and further in view of Riboldi et al. (Glucose and triglyceride excursions following a standardized meal in individuals with diabetes: ELSA-Brasil study, 2015, Cardiovascular Diabetol., pgs. 2-9) (see instant PTO-892).
The teachings of Romero-Lucas, as applied to claim 1 are addressed above.
Romero-Lucas I does not explicitly teach that the GHRH antagonist is administered before a meal.
Riboldi et al. teaches that individuals with diabetes have a larger increase in triglycerides after a meal compared to healthy individuals and take longer to return to baseline (pg. 7, left side, second paragraph). Furthermore, non-fasting triglycerides predict cardiovascular events, particularly in women (pg. 7, left side, second paragraph).
It would be obvious to modify the method of Romero-Lucas, namely administration of a GHRH antagonist to reduce TRL, by administering the GHRH antagonist before a meal. One of ordinary skill in the art would be motivated to do so in order to prevent the spike in triglycerides that occurs following mealtime and avoid medical complications like a cardiovascular event. One of ordinary skill in the art would have a reasonable expectation of success administering a known treatment for reducing TRL at the specific time when TRL needs to be reduced.
Claim(s) 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Romero-Lucas I as applied to claim 9 above, and further in view of Kim, (The definition of obesity, Korean J Fam Med. Pg 1) (seen instant PTO-892).
The teachings of Romero-Lucas, as applied to claim 9 are addressed above.
Romero-Lucas I does not explicitly teach that the subject has a body mass index (BMI) over 25, between 25-30, or over 30.
Kim teaches that the World Health Organization considers a BMI of 25-29.9 moderately obese and a BMI over greater than 30 severely obese (pg. 1, first paragraph).
It would be obvious to modify the method of Romero-Lucas to administer a GHRH antagonist, MIA-602, to treat other metabolic diseases including, obese subjects with a BMI of at least 25 as taught in Kim. Romero-Lucas I teaches treating metabolic diseases comprised of administering an effective amount of MIA-602 to reduce triglyceride-rich-lipoproteins (TRL), and obese patients with a BMI of 25-29.9 of Kim have a metabolic disorder that would benefit from a treatment that will reduce triglyceride-rich-lipoproteins levels. One of ordinary skill in the art would have a reasonable expectation of success using a known method of reducing TRL in a patient population in need of TRL reduction.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 3, 5, 6, 8, 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. US 10,201,588 B2 (hereafter the reference patent). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claims 1, 3, 8, 17, and 19, the reference patented claims are directed to a method of treating dyslipidemia (same as metabolic disease) in a mammalian subject comprised of administering GHRH antagonist, including MIA-602 (claims 1, 2, and 5). As defined by instant claim 3, administration of MIA-602 of the reference patent will naturally decrease TRL levels. Regarding instant claim 18, the claimed method of the reference patent includes treating a subject with diabetes, including type I diabetes (claims 3, 4, 6 and 7). The reference patent reads on instant claims 5 and 6 because all subjects would eat a meal at some point before the antagonist administration.
Claims 4,7, 9-12 and 16 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. US 10,201,588 B2 (hereafter the reference patent), as applied to claims 1, 3, 5, 6, 8, 17-19 in view of US 2017/0202907 A1 (hereafter Romero-Lucas I), as evidenced by Gabriel (see instant PTO-892). Although the claims of the reference patent and instant application are not identical, they are not patentably distinct.
The teachings of the reference patent as applied to instant claims 1, 3, 5, 6, 8, 17-19 are addressed above.
The claims of the reference patent do not recite that the GHRH antagonist is administered parenterally or intermittently.
Regarding instant claims 4, 9-11, and 16, Romero-Lucas I teaches administration of MIA-602 to a mammalian subject subcutaneously to treat dyslipidemia (Claim 1, [0013], [0039]); as evidenced by Gabriel, subcutaneous administration is a type of parenteral administration (abstract). Regarding claim 7, Romero-Lucas I teaches that the GHRH antagonist is administered intermittently (i.e. three times a week for 14 weeks) ([0025]). Regarding claims 2, and 9-12, Romero-Lucas I teaches dyslipidemia is a component of type 1 diabetes (T1D) ([0002]) and that MIA-602 reduces dyslipidemia in type 1 diabetes rats ([0008]).
It would be obvious to modify the method of MIA-602 administration taught by the reference patent with intermittent parenteral administration. One of ordinary skill in the art would be motivated to do so because Romero-Lucas I teaches administration of the same MIA-602 composition to the same patient population. For this reason, there would be a reasonable expectation of success. Note: the reference patent recites treating dyslipidemia in a subject that has diabetes, while instant claims 2 and 9-12 recite treating diabetes and obesity itself. However, treating dyslipidemia, as recited in claim 1 of the reference patent, reads on treating type 1 diabetes and obesity, as recited in instant claims 1-2, 9-12. The instant specification defines “treating” as reducing one or more physiological aspects of a condition ([00048]); because dyslipidemia is a component of T1D, as taught by Romero-Lucas I, treating dyslipidemia, as recited in reference patent claim 1, reads on instant claim 2. Furthermore, as discussed previously, because the patient populations of instant claims 1 and 9 are the same, the modified method of the reference patent and Romero-Lucas I also reads on “treating obesity” as recited in instant claim 9. Lastly, the modified method reads on claim 12 because all humans are obese or at risk for obesity.
Claims 13-15 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. US 10,201,588 B2 (hereafter the reference patent), as applied to 1, 3, 5, 6, 8, 17-19, in view of Romero-Lucas I, as applied to claims 4, 7, 9-12 and 16 above, in further view of Kim (see instant PTO-892). Although the claims at issue are not identical, they are not patentably distinct from each other.
The teachings of the modified method of the reference patent and Romero-Lucas I are addressed above.
The modified method of the reference patent and Romero-Lucas I do not teach that the subject has a BMI of at least 25.
Kim teaches that the World Health Organization considers a BMI of 25-29.9 moderately obese and a BMI over greater than 30 severely obese (pg. 1, first paragraph).
It would be obvious to modify the modified method of the reference patent and Romero-Lucas I to administer a GHRH antagonist, MIA-602, to treat other metabolic diseases including obese subjects with a BMI of at least 25 as taught in Kim. Romero-Lucas I teaches treating metabolic diseases comprised of administering an effective amount of MIA-602 to reduce triglyceride-rich-lipoproteins (TRL), and obese patients with a BMI of 25-29.9 of Kim have a metabolic disorder that would benefit from a treatment that will reduce triglyceride-rich-lipoproteins levels. One of ordinary skill in the art would have a reasonable expectation of success using a known method of reducing TRL in a patient population in need of TRL reduction.
Therefore, it would be obvious to one of ordinary skill in the art that the reference patent claims are patentably indistinct from the instant application.
Conclusion
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/MICHELLE CALLAHAN BUCCINI/Examiner, Art Unit 1675
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643
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