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 .
Status of the Claims
Claims 1-20 are currently pending and under examination.
Priority
The instant application 18/840,042 filed on August 20, 2024 is a 371 of PCT/US2023/013620 filed on 02/22/2023, which claims priority to, and the benefits of U.S. Provisional Application No. 63/313,272 filed on February 23, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/20/2024. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 9, 16, 17, and 19 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.
Regarding claim 9, the claim recites that the female human individual “has a BMI >20, >25, or >30, >35, >40 or >50.” The recitation is unclear because the alternatives are not set forth with clear punctuation and coordinating conjunctions. It is unclear whether applicant intends to claim each threshold separately, i.e., BMI greater than 20, 25, 30, 35, 40, or 50, or whether applicant intends a grouped limitation involving “>20, >25, or >30” and “>35, >40 or >50.” Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the BMI limitation.
Regarding claim 16, the claim recites that the child “has a BMI >20, >25, or >30, >35, >40 or >50.” For the same reasons discussed above with respect to claim 9, the recitation is unclear because the alternatives are not set forth with clear punctuation and coordinating conjunctions. It is unclear whether applicant intends to claim each BMI threshold separately or a grouped set of alternatives. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the BMI limitation.
Regarding claim 17, the claim recites the frequency of administration using unclear wording because the claim lacks a proper coordinating conjunction between the frequency alternatives, including the terms “daily” and “once.” It is unclear whether applicant intends “once daily,” “daily or once,” or a list of separate frequency alternatives. Therefore, the metes and bounds of claim 17 are not reasonably ascertainable.
Regarding claim 19, the recitation that “the agent is administered at a dose or frequency, or both, for when being used for treating another indication” renders the claim indefinite. The phrase is grammatically unclear and can be interpreted in various ways. For example, it is unclear whether the claim requires the same dose or frequency used for another indication, a dose or frequency suitable for another indication, a dose or frequency different from that used for another indication, or merely any dose or frequency known from another use of the agent. Therefore, the metes and bounds of claim 19 are not reasonably ascertainable.
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 1-20 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 specification provides in vitro data using a three-dimensional mammary epithelial cell culture model, including palmitate-induced triglyceride production and orlistat-mediated triglyceride reduction, and provides observational human data relating maternal BMI to breast-milk fat and caloric content. However, The specification does not disclose a working example in which a specific claimed agent is administered to a pregnant, lactating, postpartum, or soon-to-breastfeed female human individual and shown to improve breast milk quality as claimed. Thus, while the specification provides a basis for investigating selected agents and selected milk composition endpoints, the specification does not reasonably enable the full scope of claimed methods of administering the claimed agents to the claimed female human individuals to achieve the claimed breast milk quality improvement. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with claims 1-20 without undue experimentation.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and, (8) the quantity of experimentation necessary. All of the Wands factors have been considered and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
The present claims concern pharmacologic, biologic, nutritional, or RNA-based modulation of human breast-milk composition in female human individuals who are breastfeeding, pregnant, postpartum, overweight, obese, insulin resistant, non-diabetic, or otherwise expected to provide breast milk. The claims are broad. Claim 1 encompasses any agent that increases insulin sensitivity. Claim 2 includes multiple unrelated agents, including small molecules, nutritional compounds, antioxidants, and antibodies. Claim 5 encompasses multiple different pathways, including long-chain fatty-acid pathways, short-chain fatty-acid pathways, protein pathways, and lactose pathways. Claim 7 includes numerous unrelated agents having different mechanisms of action. Claim 14 encompasses breast injection. Claim 20 encompasses combination therapy. The claims are not limited to a specific active agent, dose, treatment duration, route, pregnancy/lactation stage, baseline milk composition, target milk component, magnitude of change, assay, safety profile, or patient subgroup.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack thereof in the art: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(a), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
One of ordinary skill in the art would have had knowledge of lactation biology, mammary epithelial metabolism, pharmacology, clinical nutrition, and drug safety in pregnancy and lactation. However, the art also demonstrates that human breast milk composition is variable and affected by many maternal, infant, and sampling-related factors.
For example, Samuel et al. (Front Nutr. 2020 Sep 16;7:576133) teaches that human milk composition is modulated by maternal, infant, and methodological factors (see e.g., p. 1, title), and that maternal BMI has been associated with human milk calorie, fat, and protein content (see e.g., p. 5, col. 2, line 11). Isganaitis et al. ( Am J Clin Nutr. 2019 Jul 1;110(1):111-120) teaches that maternal obesity is linked to changes in human milk composition and metabolites (see e.g., p. 111, conclusions). Nommsen-Rivers (Adv Nutr. 2016 Mar 15;7(2):407-14) teaches that insulin may play a role in lactation outcomes and that maternal obesity is associated with insulin resistance, but this does not establish that all insulin-sensitizing agents will improve breast-milk composition (see. e.g., p. 407, abstract). Riddle et al. (Breastfeed Med. 2016 Mar 1;11(2):80–85) teaches an association between glucose intolerance and low milk supply, showing a metabolic relationship but not a predictable method for changing milk fat, protein, or lactose content across the full claim scope (see e.g., p. 80, introduction). Nommsen-Rivers. further teach a pilot metformin study in women with low milk production and signs of insulin resistance, but the study was preliminary and did not establish a generally predictable effect of metformin, much less all insulin sensitizers, on breast-milk quality or composition (see e.g., p. 411, col. 1 line 50). Zhu et al. (Animal. 2014 Sep;8(9):1469-78) teaches that FASN inhibition by orlistat affects fatty-acid synthesis in mammary epithelial cells (see e.g., p. 1469, abstract), but this supports only a narrower fatty-acid synthesis pathway and does not make the full scope of insulin, antibody, RNA, protein, and lactose pathway interventions predictable. Eke et al. (Clin Pharmacol Ther. 2020 Oct 15;110(1):36–48) and Ren et al. (American Journal of Obstetrics & Gynecology 2021 225(1):33-42) further demonstrate that drug use and dosing in pregnant and lactating women involve clinical pharmacology and safety uncertainties, including maternal pharmacokinetics, drug transfer into milk, and infant exposure (see. Eke e.g., p. 36, abstract, Ren, e.g., p33, abstract).
Therefore, although the art provides some mechanistic and observational support for maternal metabolic status and mammary lipid synthesis being related to milk composition, the art would not have made it predictable that each and every claimed insulin sensitizer, antibody, inhibitory RNA molecule, lipid modulator, protein modulator, lactose modulator, or combination therapy would improve breast milk quality in the claimed female human individuals.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation of experimentation required:
In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the claimed invention. In the absence of working examples, the quantity of experimentation necessary to carry out the entire scope of claimed invention is high.
The specification provides meaningful guidance for a narrower palmitate/orlistat milk-fat model. In particular, the specification describes a mammary epithelial cell culture system, palmitate treatment, orlistat treatment, and measurement of triglycerides and milk-production markers. The specification also provides observational human data showing that milk from overweight or obese mothers may have increased fat and caloric content. However, the working examples do not show administration of the full range of claimed agents to pregnant, lactating, or soon-to-breastfeed human subjects to improve breast milk quality. In particular, the specification does not show administration of metformin to a claimed female human individual with resulting improvement in breast milk quality, nor does it show administration of orlistat to claimed female human individual with resulting improvement in breast milk quality. The palmitate/orlistat data are in vitro cell culture data, and the human milk data are observational rather than interventional. Therefore, the examples do not show that administration of any claimed compound to the claimed human subject produces the claimed breast milk quality improvement. The examples do not demonstrate that rosiglitazone, pioglitazone, D-chiro-inositol, catechin, N-acetyl cysteine, anti-CRFR2 antibody, anti-Fyn antibody, omeprazole, GW9662, CP-640186, growth hormone, leucine, methionine, phlorizin, phloretin, theophylline, progesterone, or inhibitory RNA molecules, alone or in combination, improve human breast milk quality across the full scope of the claims. Nor do the examples demonstrate modulation of the full scope of claimed lactose or protein pathways in human milk.
Based on the limited disclosure, the quantity of experimentation necessary to carry out the entire scope of the claimed invention would be high. One skilled in the art would need to determine, for each claimed agent or class of agents, whether it is safe for pregnant or lactating women; whether it reaches the relevant maternal or mammary target; whether it changes breast milk fat, long-chain fatty acids, short-chain fatty acids, protein, lactose, caloric content, or milk volume in the desired direction; whether the change is clinically meaningful; what dose and frequency are effective; what route is appropriate, including whether breast injection is feasible and safe; whether the treatment is appropriate before pregnancy, during pregnancy, postpartum, or during lactation; whether the agent transfers into milk; and whether maternal or infant adverse effects occur. Such experimentation would amount to a substantial research program rather than routine optimization.
In view of all the foregoing Wands factors, the specification may enable narrower embodiments involving palmitate-induced triglyceride production and orlistat-mediated triglyceride reduction in a mammary epithelial cell model, and may provide a basis for investigating metformin or other insulin-sensitizing agents in selected metabolically at-risk lactating women. However, the specification does not enable the entire scope of claims 1-20, including the full range of insulin sensitizers, antibodies, inhibitory RNA molecules, lipid modulators, protein modulators, lactose modulators, breast injection routes, pregnant and lactating subject populations, and combination therapies.
Accordingly, the full scope of claims 1-20 is not enabled by the instant specification. To overcome this rejection, Applicant should narrow the scope of the claims such that they contain a reasonable correlation with the disclosure, for example by limiting the claims to specific supported agents, specific milk-composition endpoints, specific routes of administration, and specific subject populations supported by the working examples and data.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claims 1-4, 8-9, 11-13, and 17-19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nommsen-Rivers et al. (Journal of Human Lactation 35(2), 2019, 261-271).
Nommsen-Rivers et al. disclose “Feasibility and Acceptability of Metformin to Augment Low Milk Supply: A Pilot Randomized Controlled Trial” (see e.g., p. 261, title). Nommsen-Rivers et al. teaches that “Metformin improves insulin action” (see e.g., p. 261, Abstract, Background). Nommsen-Rivers et al. further teaches that the research aim was to determine the feasibility of a metformin-versus-placebo randomized clinical trial in women with low milk production and signs of insulin resistance (see e.g., p. 261, Abstract, Research aim). Nommsen-Rivers et al. teaches that pilot trial criteria included mothers 1-8 weeks postpartum, low milk production, at least one sign of insulin resistance, and singleton, healthy, term infants (see e.g., p. 261, Abstract, method). Nommsen-Rivers et al. further teaches that eligible mothers were randomly assigned 2:1 to metformin or placebo and instructed in frequent milk removal for 28 days, with an option to stop at 14 days (see e.g., p. 261, Abstract, method).
Regarding claim 1, Nommsen-Rivers et al. teaches administering metformin to postpartum female human individuals in a breastfeeding/lactation context. Metformin is an agent that increases insulin sensitivity. The mothers in Nommsen-Rivers et al. provide breast milk to a child because the study population included postpartum mothers with low milk production and singleton, healthy, term infants. Therefore, Nommsen-Rivers et al. teaches administering to a female human individual who provides breast milk to a child an agent that increases the individual’s sensitivity to insulin.
To the extent the phrase “improving the quality of breast milk” is considered an intended result of administering the insulin-sensitizing agent, the phrase does not patentably distinguish the claimed method from Nommsen-Rivers et al., because Nommsen-Rivers et al. teaches the same administration step to the same type of female human individual in a breastfeeding/lactation context.
Regarding claim 2, Nommsen-Rivers et al. teaches metformin as the administered insulin-sensitizing agent. Claim 2 recites a group of alternative agents including metformin.
Regarding claim 3, Nommsen-Rivers et al. expressly teaches that the administered agent is metformin.
Regarding claim 4, Nommsen-Rivers et al. teaches that the mothers were not diagnosed with type 1 or type 2 diabetes. Therefore, Nommsen-Rivers et al. teaches the individual does not have diabetes.
Regarding claims 8 and 9, Nommsen-Rivers et al. teaches selecting mothers with signs of insulin resistance, including current abdominal obesity. Nommsen-Rivers et al. further teaches central obesity criteria including waist circumference of at least 90 cm and BMI of at least 30 kg/m2. Therefore, Nommsen-Rivers et al. teaches an overweight female human individual and a female human individual having a BMI greater than at least 20, 25, or 30.
Regarding claims 11 and 12, Nommsen-Rivers et al. teaches mothers 1-8 weeks postpartum in a breastfeeding/lactation context. Therefore, Nommsen-Rivers et al. teaches that the individual has given birth within the previous two years and is breastfeeding.
Regarding claim 13, Nommsen-Rivers et al. teaches Glucophage XR capsules administered with the evening meal (see e.g., p. 265, study drug). Therefore, Nommsen-Rivers et al. teaches oral administration.
Regarding claim 17, Nommsen-Rivers et al. teaches administering metformin over a 28-day treatment period, including a titration schedule in which metformin capsules are taken with the evening meal. Therefore, Nommsen-Rivers et al. teaches daily administration.
Regarding claim 18, Nommsen-Rivers et al. teaches that participants were not currently being treated with metformin before enrollment into the study. Therefore, Nommsen-Rivers et al. teaches administering metformin to an individual not otherwise prescribed for administration of metformin.
Regarding claim 19, Nommsen-Rivers et al. teaches metformin dosing of 750 mg/day, 1500 mg/day, and 2000 mg/day with the evening meal, and further teaches that the final dose used in the study was in alignment with the manufacturer’s recommendation (see e.g., p. 265, study drug). Therefore, Nommsen-Rivers et al. teaches administration at a dose or frequency used for another indication.
Accordingly, claims 1-4, 8-9, 11-13, and 17-19 are anticipated by Nommsen-Rivers et al.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-4, 8-13, and 15-19 are rejected under 35 U.S.C. 103 as being unpatentable over Nommsen-Rivers et al. (Journal of Human Lactation 35(2), 2019, 261-271).
Nommsen-Rivers et al. discloses Feasibility and Acceptability of Metformin to Augment Low Milk Supply: A Pilot Randomized Controlled Trial (see e.g. p. 261 title). Nommsen-Rivers et al. teaches that Metformin improves insulin action (see e.g. p. 261, Abstract, background). Nommsen-Rivers et al. further teaches that mothers with insulin-resistant conditions such as gestational diabetes, obesity, and polycystic ovary syndrome are at increased risk for insufficient milk production (see e.g. p. 262, Key messages). Nommsen-Rivers et al. teaches support the importance of healthy insulin action in lactation (see e.g. p. 261 Background). Nommsen-Rivers et al. teaches administering metformin to postpartum women in a breastfeeding/lactation context to evaluate whether metformin could augment milk production in women having signs of insulin resistance (see e.g. p. 263 Methods, sample).
Regarding claim 1, Nommsen-Rivers et al. teaches administering metformin to postpartum women with low milk production and signs of insulin resistance. Nommsen-Rivers et al. teaches that metformin improves insulin action and that the study was designed to evaluate metformin versus placebo in women with low milk production and signs of insulin resistance. Nommsen-Rivers et al. further teaches that eligible mothers were postpartum women with singleton, healthy, term infants and were randomly assigned to metformin or placebo. Therefore, Nommsen-Rivers et al. teaches administering an insulin-sensitizing agent to a female human individual who provides, or expects to provide, breast milk to a child.
The claimed improvement in breast milk quality would have been intrinsic to, or at least reasonably expected from, administering metformin to the same subject population because claim 1 broadly recites improving breast milk quality by administering an agent that increases insulin sensitivity, and Nommsen-Rivers et al. teaches administering metformin, an insulin-sensitizing agent, to postpartum women in a lactation context where insulin resistance is associated with lactation difficulty and healthy insulin action is important in lactation.
Regarding claim 2, Nommsen-Rivers et al. teaches metformin as the administered insulin-sensitizing agent. Claim 2 recites a group of alternative agents including metformin. Therefore, Nommsen-Rivers et al. teach the metformin species within the claimed group.
Regarding claim 3, Nommsen-Rivers et al. expressly teaches that the administered agent is metformin.
Regarding claim 4, Nommsen-Rivers et al. teaches women with signs of insulin resistance or prediabetes/insulin-resistance indicators, rather than limiting treatment only to women diagnosed with diabetes. It would have been obvious to apply the method to a non-diabetic woman with signs of insulin resistance because Nommsen-Rivers et al. identify such metabolically at-risk postpartum women as the target population for metformin treatment.
Regarding claims 8 and 9, Nommsen-Rivers et al. teaches selecting women having signs of insulin resistance and further teach that mothers with insulin-resistant conditions such as gestational diabetes, obesity, and polycystic ovary syndrome are at increased risk for insufficient milk production. Nommsen-Rivers et al. further teach central obesity criteria including waist circumference of at least 90 cm and BMI of at least 30 kg/m2. Therefore, Nommsen-Rivers et al. teach an overweight female human individual and a female human individual having a BMI greater than at least 20, 25, or 30.
Regarding claim 10, Nommsen-Rivers et al. teaches that mothers with insulin-resistant conditions such as gestational diabetes, obesity, and polycystic ovary syndrome are at increased risk for insufficient milk production. Nommsen-Rivers et al. further teaches administering metformin to postpartum women in a breastfeeding/lactation context to evaluate whether metformin could augment milk production in women having signs of insulin resistance. Although Nommsen-Rivers et al. exemplify postpartum administration, it would have been obvious to administer an insulin-sensitizing agent to a pregnant woman who expects to provide breast milk, where the pregnant woman has an insulin-resistant condition such as gestational diabetes or obesity, because Nommsen-Rivers et al. identify insulin-resistant maternal conditions as risk factors for insufficient milk production and teach the importance of healthy insulin action in lactation. Selecting administration before lactation begins would have been an obvious optimization of timing for the same maternal insulin-resistance/lactation problem.
Regarding claims 11 and 12, Nommsen-Rivers et al. teaches postpartum women in a breastfeeding/lactation context, including women providing or attempting to provide breast milk. Therefore, Nommsen-Rivers et al. teach or suggest female human individuals who have given birth and are providing breast milk to a child.
Regarding claim 13, Nommsen-Rivers et al. teaches metformin treatment in postpartum women. Metformin is conventionally administered orally. Therefore, oral administration of metformin would have been obvious as the ordinary and expected route of administration.
Regarding claims 15 and 16, Nommsen-Rivers et al. teaches maternal treatment in a breastfeeding/lactation context in which the infant receives breast milk from the treated mother. To the extent the child is overweight or has an elevated BMI, it would have been obvious to apply the same maternal intervention to a mother whose breastfed child has elevated BMI or is otherwise in need of modified nutritional exposure, because the child receives the breast milk affected by the maternal treatment. The child’s overweight or BMI status identifies the recipient of the breast milk and does not require a different agent or a different administration step than that taught or suggested by Nommsen-Rivers et al.
Regarding claim 17, Nommsen-Rivers et al. teach metformin treatment over a treatment period. Daily, repeated, or periodic administration would have been obvious because metformin is conventionally administered on a repeated dosing schedule, and selecting an appropriate dosing frequency would have involved routine optimization of a known drug dosing regimen.
Regarding claim 18, Nommsen-Rivers et al. teaches administering metformin for low milk production in women with signs of insulin resistance. Therefore, Nommsen-Rivers et al. teaches using metformin for a lactation-related purpose, rather than merely as treatment of diabetes.
Regarding claim 19, metformin had known dose and frequency regimens for other metabolic indications. It would have been obvious to administer metformin at a dose or frequency used for another indication because using known, established metformin dosing regimens would have been a predictable and routine starting point for administering the same known drug to postpartum women, with adjustment as needed for safety and tolerability.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer metformin to a female human individual who provides, or expects to provide, breast milk to a child, in order to improve or modulate a breast-milk or lactation-related property, because Nommsen-Rivers et al. teaches that metformin improves insulin action and teach administering metformin to postpartum women with low milk production and signs of insulin resistance. One of ordinary skill in the art would have had a reasonable expectation of success because Nommsen-Rivers et al. directly tested metformin in the same postpartum/lactation human population and because metformin was known for improving insulin action.
Accordingly, claims 1-4, 8-13, and 15-19 are unpatentable over Nommsen-Rivers et al.
Claims 1-4 and 8-19 are rejected under 35 U.S.C. 103 as being unpatentable over Nommsen-Rivers et al. in view of Hung et al.( US7384418B2).
Nommsen-Rivers et al. teaches administering metformin to postpartum women with low milk production and signs of insulin resistance in a breastfeeding/lactation context, as discussed above.
Nommsen-Rivers et al. does not expressly teach that the insulin-sensitizing agent is injected or locally delivered to the breast, as recited in claim 14.
Hung et al teaches devices, kits and methods for delivering an agent to a breast milk duct. Intraductal agent delivery provides an opportunity to treat a breast condition locally and avoid the pitfalls of systemic drug delivery for a local condition (see e.g., abstract). Hung teaches methods of treating a breast condition by establishing a temporary access track to a breast milk duct and delivering an agent through the track to the duct over time wherein over a defined period of time a specific amount of agent is delivered at a relatively constant rate. Establishing a track can comprise placing an indwelling unit comprising a reservoir in the lactiferous sinus of the breast duct with a lead or tube (or tether or line) to the nipple surface for retrieving or reloading the unit(see e.g. summary of invention).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer an agent locally to the breast or breast milk duct when a localized breast effect is desired, because Nommsen-Rivers et al. teaches using metformin to address an insulin-resistance-related lactation problem, while Hung et al. teaches local delivery of an agent to a breast milk duct to treat a local breast condition and avoid disadvantages of systemic drug delivery. One of ordinary skill in the art would have had a reason to use local breast-duct delivery as an alternative route when localized mammary or breast action is desired, with a reasonable expectation that direct local delivery to a breast milk duct would deliver the agent to breast duct tissue because Hung et al. expressly teaches devices and methods for delivering agents to the breast milk duct.
Accordingly, claims 1-4 and 8-19 are unpatentable over Nommsen-Rivers et al. in view of Hung et al.
Claims 1, 5-7, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Nommsen-Rivers et al. in view of Masters et al. and Zhu et al. (Animal. 2014 Sep;8(9):1469-78).
Nommsen-Rivers et al. teaches the limitations of claim 1 as discussed above.
Nommsen-Rivers et al. does not expressly teach the additional milk-composition-modulating limitations recited in claims 5, 7, and 20. In particular, Nommsen-Rivers et al. does not expressly teach administering an agent that reduces or modulates breast-milk fatty-acid/lipid content, such as conjugated linoleic acid, nor does Nommsen-Rivers et al. expressly teach administering a second agent that reduces substrate uptake, synthesis, or secretion of long-chain fatty acids; reduces substrate uptake, synthesis, or secretion of short-chain fatty acids; increases amino-acid uptake, protein synthesis, or protein secretion; or reduces uptake or synthesis of lactose.
Masters et al. teaches administration of conjugated linoleic acid (CLA) to breastfeeding women in a double-blind, placebo-controlled crossover study. Masters et al. teaches that daily CLA supplementation increased milk CLA concentration and significantly lowered milk fat content without changing milk output (see e.g., p. 133, Abstract).
Regarding claim 5, Masters et al. teaches administering CLA to breastfeeding women and achieving a change in breast-milk lipid/fat content. To the extent claim 5 requires reducing uptake, synthesis, or secretion of long-chain or short-chain fatty acids, Masters et al. teaches the practical result of lowering milk fat content in human breast milk after administration of CLA to breastfeeding women. A reduction in milk fat content would have suggested modulation of breast-milk lipid/fatty-acid content.
Nommsen-Rivers et al. and Masters et al. do not expressly identify all of the molecular targets recited in claim 6, including fatty-acid synthase, acetyl-CoA carboxylase, and lipoprotein lipase.
Zhu et al. teaches that FASN is a key enzyme for de novo fatty-acid synthesis in mammary gland and that orlistat inhibits FASN activity in mammary epithelial cells. Zhu further reports that orlistat decreased expression of ACCα, LPL, and H-FABP and reduced medium-chain fatty-acid synthesis (see e.g. p. 1469 abstract).
Regarding claim 6, Zhu et al. teaches inhibition of fatty-acid synthase activity and decreased expression of acetyl-CoA carboxylase α and lipoprotein lipase in mammary epithelial cells. These teachings correspond to the claimed inhibition of expression or activity of fatty-acid synthase, acetyl-CoA carboxylase, and lipoprotein lipase.
Regarding claim 7, Masters et al. teaches conjugated linoleic acid, and Zhu et al. teaches orlistat. Claim 7 expressly recites conjugated linoleic acid among the listed agents. Therefore, Masters et al. and Zhu et al. teach the claimed agent species.
Regarding claim 20, Nommsen-Rivers et al. teaches administering metformin, an insulin-sensitizing agent, to postpartum women with low milk production and signs of insulin resistance, and Masters et al. teaches CLA as a breast-milk lipid-modulating agent, and Zhu et al. teaches orlistat as a fatty-acid synthesis in mammary epithelial cells. Thus, the combination teaches administering an insulin-sensitizing agent together with a second agent useful for modulating breast-milk lipid/fat content.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer an insulin-sensitizing agent such as metformin and a breast-milk lipid-modulating agent such as CLA or orlistat to a female human individual who provides, or expects to provide, breast milk, because Nommsen-Rivers et al. teaches insulin resistance in a postpartum/lactation context with metformin, Masters et al. teaches CLA administration to breastfeeding women significantly lowers milk fat content without changing milk output, and Zhu et al. teaches that inhibition of FASN by orlistat decreases fatty-acid-synthesis-related genes and reduces medium-chain fatty-acid synthesis in mammary epithelial cells. One of ordinary skill in the art would have been motivated to combine the teachings because the references teach related contributors to lactation or breast-milk composition, including maternal insulin sensitivity and mammary/breast-milk lipid metabolism. One of ordinary skill in the art would have had a reasonable expectation of success because the agents were known for their respective insulin-sensitizing or lipid-modulating effects, Masters et al. directly tested CLA in breastfeeding women and observed a milk-fat-lowering effect, and Zhu et al. identified mammary fatty-acid synthesis targets and an inhibitor affecting those targets.
Accordingly, claims 1, 5-7, and 20 are unpatentable over Nommsen-Rivers et al. in view of Masters et al. and Zhu et al.
Therefore, the claimed invention is obvious to one of ordinary skill in the art at the time the application was filed, absent factual evidence to the contrary.
Conclusion
No claims are allowed.
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/G.S./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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