DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/16/25 has been entered.
Election/Restriction – Retained for the Record and Modification Noted
Species Election
This application contains claims directed to the following patentably distinct species:
Multiple and diverse conditions to be prevented or treated, ranging from any condition in claim 8, to claim 9’s still diverse muscle wasting which includes sarcopenia, anorexia, COPD, sepsis, cancer-cachexia, and AIDS, among others;
Multiple species of an amylin receptor agonist or a pharmaceutically acceptable salt thereof, which encompass natural amylin as well as synthetic chemicals having such activity; and
Multiple species of a beta-2-adreno-receptor agonist or a pharmaceutically acceptable salt thereof, which encompass natural agonists as well as synthetic chemicals having such activity.
The species are independent or distinct at least because preventing or treating one condition with one set of the agents has no overlap nor basis for similarity with preventing or treating a very different condition, e.g., COPD or AIDS vs. anorexia. In addition, these species are not obvious variants of each other based on the current record.
Applicant is required under 35 U.S.C. 121 to elect a single disclosed species, or a single grouping of patentably indistinct species, for prosecution on the merits to which the claims shall be restricted if no generic claim is finally held to be allowable. Currently, all claims are generic.
There is a search and/or examination burden for the patentably distinct species as set forth above because at least the following reason(s) apply:
Based on the wide range of possible conditions to treat, or to prevent, there are very serious search and examination burdens to examine all conditions prevented, or treated, with all possible combinations of the two classes of therapeutic agents, which includes natural agents.
Applicant is advised that the reply to this requirement to be complete must include (i) an election of a species to be examined even though the requirement may be traversed (37 CFR 1.143) and (ii) identification of the claims encompassing the elected species or grouping of patentably indistinct species, including any claims subsequently added. An argument that a claim is allowable or that all claims are generic is considered nonresponsive unless accompanied by an election.
The election may be made with or without traverse. To preserve a right to petition, the election must be made with traverse. If the reply does not distinctly and specifically point out supposed errors in the election of species requirement, the election shall be treated as an election without traverse. Traversal must be presented at the time of election in order to be considered timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are added after the election, applicant must indicate which of these claims are readable on the elected species or grouping of patentably indistinct species.
Should applicant traverse on the ground that the species, or groupings of patentably indistinct species from which election is required, are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing them to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the species unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other species.
Upon the allowance of a generic claim, applicant will be entitled to consideration of claims to additional species which depend from or otherwise require all the limitations of an allowable generic claim as provided by 37 CFR 1.141.
During a telephone conversation with Applicant Representative Kevin Dietz on 4/17/23 a provisional election was made without traverse to the following species: pramlintide and albuterol as the species, respectively, of amylin receptor agonist and beta-2-adreno-receptor agonist, and muscle wasting as the condition. Affirmation of this election must be made by applicant in replying to this Office action. It is noted that Mr. Dietz deferred to state which claims read on the elected species, and left that to the examiner, see attached telephonic interview summary.
Claims 8, 11, 12, 13, 19, and 28 are independent claims.
Claim 8 is directed to a method of preventing or treating a condition comprising delivering to a subject in need thereof a therapeutically effective amount of an amylin receptor agonist or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of a beta-2-adreno-receptor receptor agonist or a pharmaceutically acceptable salt thereof, and a pharmaceutically effective carrier.
Claim 8 and its depending claim 9, which includes muscle wasting and subspecies of such in its list are under examination for the elected species.
Claims 10-13 are directed to preventing or treating specific conditions or effects other than the elected muscle wasting so are withdrawn as being directed to a non-elected species of condition.
Claim 19 is directed to preventing or treating muscle wasting by delivering to a subject in need thereof a therapeutically effective amount of at least two different anti-catabolic agents, the latter encompassing the two elected species, so claim 19 and its dependent claims 20 and 22-24 are under examination.
Claim 21 depending from claim 19, claims both agents from beta-2-adreno-receptor receptor agonists, excluding the elected pramlintide, so is withdrawn as being directed to a non-elected species of condition.
Claims 28-30 are directed to preventing or treating excessive adiposity and are withdrawn as being directed to a non-elected species of condition.
Applicant is reminded that upon the cancellation of claims to a non-elected invention, the inventorship must be corrected in compliance with 37 CFR 1.48(a) if one or more of the currently named inventors is no longer an inventor of at least one claim remaining in the application. A request to correct inventorship under 37 CFR 1.48(a) must be accompanied by an application data sheet in accordance with 37 CFR 1.76 that identifies each inventor by his or her legal name and by the processing fee required under 37 CFR 1.17(i).
The examiner notes that the claims as amended narrow the elected muscle wasting species to “muscle wasting associated with aging”.
Claim Status
Claims 8, 9, 31-33 are pending.
Claims 1-7, 10-30 are cancelled.
Claims 8, 9, 31-33 have been examined.
Claims 8, 9, 31-33 are rejected.
Priority
The instant application, filed 03/01/2021 is a Continuation of 15506392 , filed 02/24/2017, now abandoned and having 2 RCE-type filings therein
15506392 is a National Stage entry of PCT/US2015/046725 , International Filing Date: 08/25/2015
PCT/US2015/046725 Claims Priority from Provisional Application 62147168 , filed 04/14/2015
PCT/US2015/046725 Claims Priority from Provisional Application 62041223 , filed 08/25/2014.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 10/16/25 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
Drawings
The drawings are objected to because 1) the units in Figures 1-3, and 5 are in “um” which is not an ordinary and customary amount or concentration, and 2) in Fig. 1B the last two treatments, of “Pr/Abl” have different bar heights but the same legend amount, “1/0.25um”. 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.
The corrections must also indicate where specific support for any amendments/corrections is/are found in the application as filed.
Specification
The disclosure is objected to because of the following informalities: in the first full paragraph on page 28, referring to Fig 1 top panel but not the bottom panel, i.e., Fig. 1B, the units are in “mm” which is not an ordinary and customary amount or concentration and which differs from the units shown in the Figure.
Appropriate correction is required. The correction must also indicate where specific support for any amendments/corrections is/are found in the application as filed.
Claim Interpretation – Retained for the Record and Updated
The claim limitations are given their broadest reasonable interpretation (BRI) consistent with the specification, MPEP 2111, and under the BRI, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification, MPEP 2111.01.
Independent claim 8 is directed to a method of treating muscle wasting associated with aging comprising delivering to a subject in need thereof a therapeutically effective amount of an amylin receptor agonist or pharmaceutically acceptable salt thereof and a therapeutically effective amount of a beta-2-adreno-receptor agonist or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, amended 1/6/25 to add that the delivering is daily to a human subject in need thereof, and that the therapeutically effective amount of the amylin receptor agonist or a pharmaceutically acceptable salt thereof comprises “a human equivalent dose of either 15mg/kg pramlintide or 60mg/kg pramlintide” and that the therapeutically effective amount of the beta-2-adreno-receptor agonist or a pharmaceutically acceptable salt thereof comprises “a human equivalent dose of 12 mg albuterol,” and “wherein the subject is an elderly subject.”
As previously noted regarding actual data, it was noted that the rodent evaluation included a single amount of 12 mg albuterol without regard for body weight of the subject, see In Vivo Pharmacology Studies 2 and 3 Combined (FIGS. 11-14), and in such studies this compound was administered on a daily basis.
The transition phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps., see MPEP 2111.03 I.
Retained for the record, as previously stated on page 12 of the specification, “As used herein, the term “subject,” or “patient,” includes humans, mammals (e.g., mice, rats, pigs, cats, dogs, and horses), and ayes [sic, aves?]. Typical subjects to which compounds of the present disclosure may be administered will be mammals, particularly primates, especially humans. For veterinary applications, a wide variety of subjects will be suitable, e.g., livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. For diagnostic or research applications, a wide variety of mammals will be suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and swine such as inbred pigs and the like.” Thus, the claim 8 subject that is in need of the claimed method of treating muscle wasting associated with aging can be any of the animals encompassed by this exemplary listing from the specification, as well as other animals not listed that are in need of the claimed method. The examiner notes that the weight differences among subjects are substantial, yet the dosage for albuterol is fixed in claim 8, at 12 mg. See Nair and Jacob, J Basic Clin Pharma 2016;7:27-31, previously provided, Table 1, page 29, which sets forth weight differences of some common subjects having substantially different weight and body surface areas (BSAs). As noted herein, applicant now limits the method to a human subject in need thereof, this subject “is an elderly subject.”
As to treating “muscle wasting associated with aging,” based on the use of the claim term “aging” in the specification, as this is applied with muscle wasting, and as distinguished by alternative language in para 76 (all para numbers of the corresponding PG PUB US 2021017794) from a decrease in muscle mass that often occurs “associated [with] some conditions or diseases or treatments for those conditions or diseases” – this interpreted as a disavowal of the full scope of the plain meaning that could include these as well as a broader interpretation of any muscle wasting throughout the aging process, particularly given the use of “aging” related to loss of muscle mass in para 157 (“As aging progresses, mammals normally lose muscle mass and replace this with WAT … However, relative to untreated elderly animals, the combination of albuterol/pramlintide was effective in inhibiting the natural decrease in muscle mass and increase in WAT so widely seen in aging”), and also the example in which elderly mice are compared with young mice, see In Vivo Pharmacology Studies 2 and 3 Combined (FIGS. 11-14), “muscle wasting associated with aging” is interpreted to be limited to muscle wasting that occurs in elderly subjects that is typical in the aging process, such as sarcopenia, and not to muscle wasting due to specific disease processes or treatments thereof, i.e., specific disease processes or treatments thereof that result in muscle wasting, such as cancer or other specific diseases.
The examiner notes for the record that applicant agreed to the bolded interpretation portion above on page 5 of the 1/6/25 Remarks.
Per above, claim 8 as amended 1/6/25 now specifies the method delivering daily to a human subject in need of treating muscle wasting associated with aging, a therapeutically effective amount of 1) amylin receptor agonist or a pharmaceutically acceptable salt that comprises a human equivalent dose of either 15mg/kg pramlintide or 60mg/kg pramlintide, and beta-2-adreno-receptor agonist or a pharmaceutically acceptable salt thereof that comprises a human equivalent dose of 12 mg albuterol, wherein the subject is an elderly subject.
The 1/6/25 Remarks, page 5, state “no new matter was added” and points to pages 5 and 38-40 of the specification for support of “elderly subject” and “for example” to pages 7, 11, 12 and 26 of the specification for support for the “human subject.” No mention was made of “human equivalent dose” in applicant’s Remarks, nor how this was known or determined for the relevant class of “elderly subject” being administered the claimed agents in claim 8. The examiner notes that “human equivalent dose” was taught in Nair and Jacob, J Basic Clin Pharma 2016;7:27-31, previously provided, however this teaches human equivalent dose (HED) conversion factors between other animals and humans, see Table 1 page 29, where these factors are further modified based on size of animal, see page 29 text, beginning at “However, it must be borne in mind that the km factor varies across animal species and increases proportional to W2/3 within a species as body weight increases.” Also as to the Table 1 conversion factors, these are focused for healthy volunteers, see Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, CDER 2005, 30 pages (CDER), previously provided, where at its Table 1 on page 7 are found essentially the same conversion factors as in the Nair and Jacob Table 1.
Also on page 5 “Applicant acknowledges the Examiner’s interpretation that alleges “muscle wasting associated with aging” is interpreted to be limited to muscle wasting that occurs in elderly subjects that is typical in the aging process, such as sarcopenia, and not to muscle wasting due to specific disease process or treatments thereof (such as those treatments or diseases that result in muscle wasting.”
Considering what applicant now claims, after further consideration and evaluation of support as it might exist in the application as filed, the examiner remains perplexed as to the support as well as the metes and bounds and clarity of what is claimed, and makes the following rejections given claim 8 as amended 1/6/25, which are directed to the same subject matter of the latest claim set of 10/16/25.
Claim Rejections - 35 USC § 112 - Indefiniteness
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.
Response to Arguments
Applicant's arguments filed 10/16/25 have been fully considered but they are not persuasive.
Applicant’s argues, pages 4-5, that Table 1 of the FDA Guidance entitled “U.S. Food and Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 2005, available at https://www.fda.gov/media/72309/download, previously referenced in previous rejection and previously provided, “includes calculating the human equivalent dose (HED) by converting the no observed adverse effect levels (NOAELs) determined in animal studies into HEDs using the Body Surface Area method. Specifically, Table 1 of this FDA Guidance provides conversion factors and divisors recommended by the FDA as the standard values used to convert animal doses to human equivalent doses based on body surface area. Accordingly, Applicant submits that a person of ordinary skill in the art would follow this FDA Guidance to determine human equivalent doses from experimental animals.”
This is not persuasive because 1) the Guidance is for “Adult Healthy Volunteers”, not elderly humans in need of the claimed therapy, and additionally 2) because the calculated doses are for starting levels, the Guidance on page 2 stating, “Toxicity should be avoided at the initial clinical dose. However, doses should be chosen that allow reasonably rapid attainment of the phase 1 trial objectives (e.g., assessment of the therapeutic’s tolerability, pharmacodynamic or pharmacokinetic profile),” even the HED as calculated by one or more approaches would not normally be the ultimate therapeutic dose, see page 4 which states in part, “A safety factor should then be applied to the HED to increase assurance that the first dose in humans will not cause adverse effects. The use of the safety factor should be based on the possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than predicted by the animal models, that bioavailability may vary across species, and that the models tested do not evaluate all possible human toxicities. For example, ocular disturbances or pain (e.g., severe headaches) in humans can be significant dose-limiting toxicities that may go undetected in animal studies. In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor” (underlined emphasis added). Overall, it remains unclear what HED would be suitable and effective for the claimed subject group.
Regarding applicant’s arguments against the rejection below based on the age limit for “elderly subject,” this is unpersuasive because applicant has not stated why the NIH Style Guide, preferring “older adults” – this referring to a person 65 years or older, should be used instead of the alternative of the two noted ordinary and customary meanings, of human subjects 60 years or older (and secondarily nor that “elderly subject” is equivalent to “older adult(s)”), AND clearly on page 1 of the NIH Style Guide it is stated:
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That is, even this reference provided by applicant to prove a point clearly states “definitions of older adulthood vary.” Again, applicant’s arguments are unpersuasive here at least because the reference applicant applies itself states that definitions of older adulthood vary, and per below this remains unclear so the claims remain indefinite.
Claims 8, 9 and 31-33 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.
Applicant now claims in claim 8 administering to an elderly human subject a human equivalent dose (HED) of either 15mg/kg pramlintide or 60mg/kg pramlintide, and a human equivalent dose of 12 mg albuterol on a daily basis.
Nair and Jacob, J Basic Clin Pharma 2016;7:27-31, previously provided, teaches human equivalent dose (HED) conversion factors between other animals and humans, see Table 1 page 29, however these factors are further modified based on size of animal, see page 29 text with example, beginning at “However, it must be borne in mind that the km factor varies across animal species and increases proportional to W2/3 within a species as body weight increases.” No weight of mice used in applicant’s examples was or is applied to modify the Table-based factor after its calculation. Also and critically as to the Table 1 conversion factors, these are focused for healthy volunteers, see Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, CDER 2005, 30 pages, where at its Table 1 on page 7 are found essentially the same conversion factors as in the Nair and Jacob Table 1.
There are no HED factors set forth in either the Nair and Jacob reference nor the CDER reference for elderly human subjects. To the contrary, Sharma and McNeill, British Journal of Pharmacology (2009), 157, 907–921, previously provided, not only broadly states that “principles of inter-species dose extrapolation are poorly understood and applied,” page 907, and when it comes to elderly subjects, “the major factors to specifically address when deriving drug doses in the elderly are co-morbidities and polypharmacy.” This suggests that there is no one HED that is to be applied to an elderly human subject. Further supporting variability and differences for elderly human subjects, Shah, Br J Clin Pharmacol 58:5 452–469, 2004, entitled, “Drug development and use in the elderly: search for the right dose and dosing regimen,” previously provided, reviews age-related changes in pharmacology, starting on page 454, see Table 2 and text, and the following statements, “When age-related changes in pharmacokinetics are put in perspective, it is evident that gender, ethnicity or the genotype of a patient frequently has a far greater effect,” page 456, and “Age-related changes in pharmacokinetics are typically investigated in a panel of subjects aged ≥ 65 years and who are otherwise healthy – a population that is not easy to find. Subjects who have renal or hepatic impairment are excluded from randomization and the influence of these two variables is investigated in separate studies. The pharmacokinetic parameters in this elderly panel are compared with those from a younger panel (about 30–40 years of age). It is neither possible nor intended to generalize, but in broad terms, the mean data from a number of drugs show that changes in pharmacokinetics due to age per se are very modest (of the order of 20–40%) when compared with the influences of other covariates such as food, gender, comorbidity, comedications and genetic factors (of the order of 50–300%). There are of course exceptions to this.”
Given the above, and the absence of guidance directing one of ordinary skill in the art to what particular HED applicant has identified or teaches or focuses on for the method of claim 8 for an elderly human subject in general, or having a particular state of health/comorbidity and/or comedication (such as insulin), one of ordinary skill in the art cannot reasonably understand what the HEDs are for what is being claimed, which includes the preamble requirement of treating muscle wasting associated with aging, which comprises sarcopenia per claim 31, therefore cannot reasonably understand the metes and bounds of what is claimed in claim 8 and claims 9 and 31-33 depending from claim 8.
Separately and in addition to the above, applicant has not specified the age limit for “elderly subject”, this subject being a human per claim 8, and there are two ordinary and customary meanings, see Google search screen shot, 2025, 1 page. It is unclear whether what is being claimed encompasses human subjects aged 60 or older, or alternatively aged 65 or older. Claim 8 and claims 9 and 31-33 depending from claim 8 are rejected on this basis.
Claim Rejections - 35 USC § 112 Enablement
Response to Arguments
Applicant's arguments filed 10/16/25 have been fully considered but they are not persuasive.
Applicant provides largely the same arguments and assertions for all of the 35 USC 112 rejections, so much of what is below in this Response to Arguments repeats much of what is set forth above.
Applicant’s argues, pages 4-5, that Table 1 of the FDA Guidance entitled “U.S. Food and Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 2005, available at https://www.fda.gov/media/72309/download, previously referenced in previous rejection and previously provided, “includes calculating the human equivalent dose (HED) by converting the no observed adverse effect levels (NOAELs) determined in animal studies into HEDs using the Body Surface Area method. Specifically, Table 1 of this FDA Guidance provides conversion factors and divisors recommended by the FDA as the standard values used to convert animal doses to human equivalent doses based on body surface area. Accordingly, Applicant submits that a person of ordinary skill in the art would follow this FDA Guidance to determine human equivalent doses from experimental animals.”
This is not persuasive because 1) the Guidance is for “Adult Healthy Volunteers”, not elderly humans in need of the claimed therapy, and additionally 2) because the calculated doses are for starting levels, the Guidance on page 2 stating, “Toxicity should be avoided at the initial clinical dose. However, doses should be chosen that allow reasonably rapid attainment of the phase 1 trial objectives (e.g., assessment of the therapeutic’s tolerability, pharmacodynamic or pharmacokinetic profile),” even the HED as calculated by one or more approaches would not normally be the ultimate therapeutic dose, see page 4 which states in part, “A safety factor should then be applied to the HED to increase assurance that the first dose in humans will not cause adverse effects. The use of the safety factor should be based on the possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than predicted by the animal models, that bioavailability may vary across species, and that the models tested do not evaluate all possible human toxicities. For example, ocular disturbances or pain (e.g., severe headaches) in humans can be significant dose-limiting toxicities that may go undetected in animal studies. In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor” (underlined emphasis added). Overall, there is no basis in Applicant’s arguments that by referring to general approaches to calculating NOAELs and HEDs for studies on healthy human volunteers, when applied to the instant application (where HEDs were not referenced nor factors referred to) and claims, these directed to therapeutically effective levels for an elderly human subject in need of the claimed treatment method, that applicant is enabled for what is instantly claimed.
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 8, 9 and 31-33 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
This rejection pertains both to the elected species and beyond these.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one
considers the following factors to determine whether undue experimentation is required (also recited in
MPEP 2164.01(a)): (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. Some
experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The factors are summarized and analyzed below:
(A) The breadth of the claims: claim 8 is directed to treating an elderly human subject, the method delivering daily to a human subject in need of treating muscle wasting associated with aging, a therapeutically effective amount of 1) amylin receptor agonist or a pharmaceutically acceptable salt that comprises a human equivalent dose of either 15mg/kg pramlintide or 60mg/kg pramlintide, and beta-2-adreno-receptor agonist or a pharmaceutically acceptable salt thereof that comprises a human equivalent dose of 12 mg albuterol, wherein the subject is an elderly subject.
For the purposes of this rejection, an elderly human subject is interpreted as a living human person aged at least 65 years old.
(B) The nature of the invention: in the medical field, including administering compounds and formulations thereof that afford therapeutically treating an existing condition, disease or disorder, here muscle wasting associated with aging, interpreted above to include sarcopenia but not to diseases such as cancer that also result in decrease in muscle mass that can be encompassed by “muscle wasting”.
(C) The state of the prior art: Amylin is a natural amylin receptor agonist, and pramlintide is one of many synthetic amylin receptor agonists. Amylin slows gastric emptying and promotes satiety, thereby preventing post-prandial spikes in blood glucose levels. Other properties and activities reported in the art are summarized below in the discussion of the amount of direction provided by the inventor.
Beta-2 Adrenergic agonists, such as the elected albuterol, are known to act mainly on the
smooth muscle of the vasculature, bronchial tree, intestines and uterus, and find the majority of
their use in treating or preventing symptoms of asthma, although particularly at high doses can
result in liver toxicity, LiverTox: Clinical and Research Information on Drug Induced Liver Injury
[Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases,
2012-. Beta-2 Adrenergic Agonists. [Updated 2017 Sep 11], previously provided.
(D) The level of one of ordinary skill : the level of ordinary skill in the art is moderately high; a representative person of ordinary skill in the art has at least a B.S. degree in biological, chemical, pharmaceutical major study, and 2 years of experience in the field of medical research or is a physician with at least one year experience in relevant clinical practice.
(E) The level of predictability in the art: Dosages to achieve a desired therapeutic effect are generally extrapolated from one species to another species based on calculations that can include or consider body weight, body surface area (BSA), and/or pharmacological considerations including compartment modeling such as how the dose is related to blood and tissue concentrations. See for example Nair and Jacob, J Basic Clin Pharma 2016;7:27-31 in its entirety. While not necessarily predictable to an exact degree, it is understood in the art that when considering dosage for subjects that are larger/heavier subjects having greater BSA than the species for which an evaluation was made, an increase in the dosage, such as measured by weight of the therapeutic agent to be delivered, is reasonable in order to achieve a desired therapeutic effect.
However, for the currently claimed elderly human subject(s) the human equivalent doses (HED) is not well-established. Sharma and McNeill, British Journal of Pharmacology (2009), 157, 907–921, not only broadly states that “principles of inter-species dose extrapolation are poorly understood and applied,” page 907, and when it comes to elderly subjects, “the major factors to specifically address when deriving drug doses in the elderly are co-morbidities and polypharmacy.” This suggests that there is no one HED that is to be applied to an elderly human subject, Further supporting variability and differences for elderly human subjects, Shah, Br J Clin Pharmacol 58:5 452–469, 2004, entitled, “Drug development and use in the elderly: search for the right dose and dosing regimen,” reviews age-related changes in pharmacology, starting on page 454, see Table 2 and text, and the following statements, “When age-related changes in pharmacokinetics are put in perspective, it is evident that gender, ethnicity or the genotype of a patient frequently has a far greater effect,” page 456, and “Age-related changes in pharmacokinetics are typically investigated in a panel of subjects aged ≥ 65 years and who are otherwise healthy – a population that is not easy to find. Subjects who have renal or hepatic impairment are excluded from randomization and the influence of these two variables is investigated in separate studies. The pharmacokinetic parameters in this elderly panel are compared with those from a younger panel (about 30–40 years of age). It is neither possible nor intended to generalize, but in broad terms, the mean data from a number of drugs show that changes in pharmacokinetics due to age per se are very modest (of the order of 20–40%) when compared with the influences of other covariates such as food, gender, comorbidity, comedications and genetic factors (of the order of 50–300%). There are of course exceptions to this.”
(F) The amount of direction provided by the inventor: The specification Background teaches of
the epidemic of obesity and excess body fat accumulation being tightly linked to the
prevalence of insulin resistance, type 2 diabetes, dyslipidemia, CVD and other disorders.
There is stated the role of white adipose tissue (WAT) is to store lipids, noting that in
syndromes such as obesity and insulin resistance, WAT adipose tissue can be a source of
immune “dysfunction” and chronic inflammation that is linked to disease etiology. Brown
adipose tissue (BAT) on the other hand is the opposite and its prime function is to bum off
excess energy in the form of heat. In the BAT science area, this is termed uncoupling the
energy transfer (of electrons) to make ATP (energy currency of the cell), to instead dissipate
excess energy (adipose tissue) as heat via the uncoupling protein 1 (UCP1) molecule. Thus
there is a need to reduce obesity and excess body fat, in particular WAT. The specification
more broadly teaches treating a condition, the condition can be selected from the group
consisting of: muscle wasting, sarcopenia, a muscle wasting-related disorder, a muscle
wasting-related disease, a muscle wasting-related condition, diabetes, insulin-resistance
syndrome, cancer-cachexia, COPD, AIDS, congestive heart failure, sepsis, anorexia,
pulmonary disease, excess adiposity, an excess adiposity-related disorder, an excess
adiposity-related disease, an excess adiposity-related condition, lipodystrophy, nonalcoholic
steatohepatitis, a cardiovascular disease, polycystic ovary syndrome, metabolic syndrome,
and a combination thereof. The treating includes administering the two claimed agent
classes, and more broadly two different anti-catabolic agents. See paras 2-5.
Examples 1-3 are directed to studying the effects of the claimed agents on enzymes and
pathways related to protein synthesis and degradation, see paras 121-129. Paras 124-128
summarize the results of a number of prior art references regarding “… a complex scenario
wherein an intricate network of signaling pathways regulates the size of myofibers and the
contractile performance of muscle. These different pathways crosstalk and modulate one
another at different levels, coordinating protein synthesis and degradation simultaneously.
Highlighted here is the involvement of the major pathway (IGF1-Akt-Fox0, myostatin) in
muscle atrophy/building and how using these biomarkers can improve the understanding how
a combination therapy works to promote muscle-building,” para 124.
Additionally, broad and generic disclosures are found in the specification as to the effect of
the claimed combination.
Although human subjects were stated among a long list of subjects, and elderly mice were evaluated, there is no mention of human equivalent dose (HED), nor any particular HED broadly for elderly human subjects nor for any particular HED for a human elderly subject having a particular comorbidity or taking other medications, for treating muscle wasting associated with aging, or more specifically for sarcopenia.
(G) The existence of working examples: Example 1 demonstrated a more than additive effect of
pramlintide and albuterol on mTOR activation in an in vitro assay, mTOR having a role in protein synthesis1. Example 2 evaluated these two agents combined increased SK6 activity greater than each alone, SK6 disclosed as having been implicated as an important positive regulator of biological processes, such as cell growth, proliferation, and regulating ribosomal activity and protein synthesis. Example 3 evaluated the agents’ effects on the RMS-13 cell’s myoblast transcriptome, these involved in the intricate network of signaling pathways that regulates myofiber size and muscle contractile performance. For most that were measured, there was no change, and for one noted in para 129, MuRF1, vs. PBS control, the statistical result was p=0.068, so below the 0.05 probability standard normally used to establish statistical significance. Example 5 demonstrated that pramlintide alone lowered myostatin secretion in FMR-13 cultured cells, leading applicants to hypothesize that amylin alone and in
combination with albuterol is able to directly suppress myostatin secretion in myoblasts. The murine in vivo studies demonstrated that young mice responded to the claimed combination by increasing muscle mass, however the effect was much lower in older mice, paras 136-157. The example comparing young with aged mice demonstrated a modest retention of muscle mass in aged mice when compared with aged mice that did not receive treatment. This example provided daily doses for 5 months. Other examples pertained to obesity, and effects of insulin and calcitonin.
Further as to both guidance and working examples, the examiner notes that what is claimed to be administered to an elderly human subject – the HED of either 15 mg/kg pramlintide or 60mg/kg pramlintide, and human equivalent dose of 12 mg albuterol, when converted per the Tables of Nair and Jacob or CDER, referenced above, result in 1.2 or 4.8 mg/kg for pramlintide. For a 50 kg elderly human subject (10 kg less than the 60 kg human subject per the Table) this results in a daily dosage of 60 mg or 240 mg of pramlintide per day. NDA 21-332 for SYMLIN®, 2005, 26 pages, previously provided, which is for pramlintide acetate for injection, on page 16 teaches that “Single 10 mg doses of SYMLIN (83 times the maximum dose of 120 μg) were administered to three healthy volunteers. Severe nausea was reported in all three individuals and was associated with vomiting, diarrhea, vasodilatation, and dizziness.” The examiner notes that there is neither teaching nor evidence to counter the very high probability that when administering to an elderly subject these HED calculated-by-table-and-not-further-modified doses that are, respectively 6 and 24 TIMES GREATER THAN the 10 mg pramlintide acetate doses that in three healthy volunteers resulted in severe nausea, associated with vomiting, diarrhea, vasodilatation, and dizziness, that there would be a suitable treatment therapy as claimed in claim 8, 9, and claims 31-33 depending from it, at least based on highly likely cessation of therapy at these doses due to such very highly probable adverse effects. Applicant has not addressed how to effectuate treatment as claimed while also, somehow, countering severe adverse effects at doses at or near those calculated from the above-indicated Table, nor whether if by adjusting the HED downward for any number of reasons such as in CDER, so as to not cause severe side effects, a ‘therapeutic’ effect for elderly human subjects in need of the claim 8 treatment would be effective for what is claimed (given the substantially higher dosing in the only evaluated rodent species). The lack of guidance and the lack of working examples for what is claimed, including any HED in this range (or a lower range if various CDER factors were to have been applied – this neither taught nor suggested), are critical in the instant lack of enablement rejection.
The examiner also notes that the Table-calculated HED is for a healthy human subject, and for albuterol, converting from 12 mg in a mouse to such human, is 0.97 mg (regardless of weight of the human subject and before any adjustments as set taught in Nair and Jacob or CDER). Whether this would contribute to effectiveness for what is claimed for very heavy weight elderly human individuals as well as for lower weight elderly human individuals remains unanswered.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
As to claim 8 and claims 9 and 31-33 depending from claim 8, at least based on the very highly likely adverse effects of administering pramlintide at the claimed dosage (as calculated above), multiple times greater than the 10 mg pramlintide acetate doses that in three healthy volunteers resulted in severe nausea, associated with vomiting, diarrhea, vasodilatation, and dizziness, to an elderly subject that may have variable response in any case due to age combined with other factors including food, gender, comorbidity, comedications and genetic factors, the quantity of experimentation to use the invention would be highly excessive and undue (if achievable at all, even if HED were lowered based on any number of factors in CDER, this per above raising an issue of therapeutically effective amount for the claimed elderly human subject group). That claims 31-33 provide for subcutaneous administration does not mitigate or lessen this basis given that subcutaneous administration is what is set forth in NDA 21-332 for SYMLIN®, 2005, 26 pages.
Based on the above, considering the evidence and factors set forth above, undue experimentation would be required to enable the claims commensurate with the scopes claimed for elderly human subject(s). As such independent claim 8 is rejected for lack of enablement as to its scope, and claims 9 and 31-33 depending from claim 8, also are rejected based upon the reasoning applied to claim 8 above.
Claim Rejections - 35 USC § 112 – Written Description
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.
Response to Arguments
Applicant's arguments filed 10/16/25 have been fully considered but they are not persuasive.
Applicant provides largely the same arguments and assertions for all of the 35 USC 112 rejections, so much of what is below in this Response to Arguments repeats much of what is set forth above.
Applicant’s argues, pages 4-5, that Table 1 of the FDA Guidance entitled “U.S. Food and Drug Administration (FDA). Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers, July 2005, available at https://www.fda.gov/media/72309/download, previously referenced in previous rejection and previously provided, “includes calculating the human equivalent dose (HED) by converting the no observed adverse effect levels (NOAELs) determined in animal studies into HEDs using the Body Surface Area method. Specifically, Table 1 of this FDA Guidance provides conversion factors and divisors recommended by the FDA as the standard values used to convert animal doses to human equivalent doses based on body surface area. Accordingly, Applicant submits that a person of ordinary skill in the art would follow this FDA Guidance to determine human equivalent doses from experimental animals.”
This is not persuasive because 1) the Guidance is for “Adult Healthy Volunteers”, not elderly humans in need of the claimed therapy, and additionally 2) because the calculated doses are for starting levels, the Guidance on page 2 stating, “Toxicity should be avoided at the initial clinical dose. However, doses should be chosen that allow reasonably rapid attainment of the phase 1 trial objectives (e.g., assessment of the therapeutic’s tolerability, pharmacodynamic or pharmacokinetic profile),” even the HED as calculated by one or more approaches would not normally be the ultimate therapeutic dose, see page 4 which states in part, “A safety factor should then be applied to the HED to increase assurance that the first dose in humans will not cause adverse effects. The use of the safety factor should be based on the possibility that humans may be more sensitive to the toxic effects of a therapeutic agent than predicted by the animal models, that bioavailability may vary across species, and that the models tested do not evaluate all possible human toxicities. For example, ocular disturbances or pain (e.g., severe headaches) in humans can be significant dose-limiting toxicities that may go undetected in animal studies. In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor” (underlined emphasis added). Overall, there is no basis in Applicant’s argument