Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
Filing Receipt and Priority
The filing receipt mailed 09/06/2024 states that the instant application is a 371 of PCT/EP2022/069015, filed 07/07/2022. The filing receipt states the instant application claims foreign benefit of a EPO 21305941.3 filed 07/08/2021.
The certified document supports the instant application. Therefore, the effective filing date is 07/08/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted 12/29/2023 has been considered.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections
Title
The use of “New” in the title of the instant application is improper. Examiner requires amending the title to remove ‘New”.
Claim Objections
Claim 13 is objected to. Claim 13 states “The [method] according to claim 6, wherein the acetoacetate (AcAc) is ethyl acetoacetate or sodium acetoacetate.”
The claim is missing “method” in between “The” and “according”.
Critically, the use of “ethylacetoacetate” and “sodium acetoacetate” is improper because acetoacetate is a known compound, specifically an anion, with a specific structure. Ethylacetoacetate and sodium acetoacetate are distinct compounds (or a salt in the case of sodium acetoacetate) with different structures than acetoacetate.
The instant specification on p. 4 states “According to the invention, the term acetoacetate (AcAc) is used here to denote the acetoacetate and all the derivatives of acetoacetate which includes but are not limited to butyl acetoacetate, ethyl acetoacetate, methyl acetoacetate, isobutyl acetoacetate, isopropyl acetoacetate, n-propyl acetoacetate, sodium acetoacetate and n-butyl acetoacetate.”
While applicant has defined the term “acetoacetate” to include derivatives listed above, the claim would be in better form if claim 6 stated “a therapeutically effective amount of acetoacetate (AcAc) or derivative thereof”.
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.
Scope of Enablement – Prevention, Acidosis Related Diseases
Claims 6 and 8-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating of sepsis, septic shock, CO intoxication, a hemopathy, leukemia and lymphoma, metformin intoxication, acute liver failure, and pheochromocytoma, does not reasonably provide enablement for prevention in general and prevention of the above listed conditions. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The following Wands Factors have been considered if not explicitly stated.
(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.
Breadth of the claims
Claim 6 states “A method for treating an acidosis related disease…”.
The instant specification defines “treatment” and “treat” to refer to “both prophylactic or preventative treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.” Therefore, “treatment” and “treating” include prevention.
The term “acidosis related disease” is defined as “diseases with acidosis that is to say diseases causing increased acidity in the blood and other body tissues.” This is not a closed definition and includes diseases having acidosis which are not mentioned within the instant disclosure. Similarly, “lactic acidosis related diseases” is not defined. The specification gives examples of “lactic acidosis related diseases” but does not use closed language regarding these terms (See 112(b) rejection below). Therefore, the full scope of the claims is not known.
Nature of the invention
The claims are drawn to a clinical method of treatment.
State of the prior art
Formulations comprising acetoacetate are contemplated within the art. Additionally, application of these formulations to treat acidosis are also known within the art. See Veech cited below. However, the Veech formulation contemplates a solution comprising acetoacetate and other ingredients. These teachings are distinct from the instant disclosure in that the instant disclosure teaches administration of lithium acetoacetate and only lithium acetoacetate.
Further, Veech contemplates administration of its composition for metabolic acidosis, along with other unrelated conditions. Veech does not explicitly discuss administration to treat any of the claimed “acidosis related diseases” of claim 9, but one of ordinary skill would find it obvious to treat the acidosis related to or caused by the claimed conditions. See Gutierrez, Prockop, Chan, Pham, Heinig, and Manger in the 102 and 103 rejections below for references that connect the claimed “acidosis related diseases” to metabolic acidosis, or specifically, lactic acidosis.
Working Examples
The examples are drawn to tests where lithium acetoacetate and only lithium acetoacetate was administered to treat cells in induced lactic acidosis conditions. Applicant finds that “AcAc protects [peripheral blood mononuclear cells] from septic shock patients from death by apoptosis.” From this, it can be shown that only sepsis or septic shock conditions have been tested in the instant disclosure. There are no tested conditions that represent the other claimed conditions, excluding sepsis and septic shock.
There is no evidence that shows administering acetoacetate prior to the onset of acidosis is effective in preventing acidosis related diseases.
Quantity of Experimentation
Considering the above, there is a significant level of unpredictability should one of ordinary skill attempt to practice the instant methods within their scope. One of ordinary skill in the art would have an undue burden of experimentation in order to practice the claimed methods.
Additionally, while the art makes obvious the simple method of administering acetoacetate to other conditions, the instant specification is not enabled for the full scope of “acidosis related diseases.”
Claim Rejections - 35 USC § 112(b)
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.
Indefinite – Indefinite Terms
Claims 6 and 8 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 6 states “acidosis related disease”. The instant specification on p. 2 states “As used herein, the term ‘acidosis related diseases’ relates to diseases with acidosis that is to say diseases causing increased acidity in the blood and other body tissues.”
While the instant specification attempts to define “acidosis related disease”, the definition does not use closed language, does not list specific diseases which are acidosis related diseases, and does not teach methods to determine which diseases are or are not acidosis related diseases.
The instant specification in its definition of “acidosis related disease” states “relates to”. This is not definitive language as it includes any number of diseases that may present acidosis. Additionally, the specification states “For example, acidosis related diseases are…”. This language is open-ended and would not convey the metes and bounds of the claim to one of ordinary skill in the art. The instant disclosure also fails to teach any methods with which one of ordinary skill in the art would be able to determine which diseases are “acidosis related diseases.”
Claim 8 states “lactic acidosis related disease”. The term is undefined within the instant specification and applicant has not provided guidance to determine which, if any, diseases are “lactic acidosis related”. One of ordinary skill in the art would not know the metes and bounds of the claims considering the lack of definition and guidance.
Considering the above, one of ordinary skill in the art would not know the metes and bounds of the claims.
Antecedent Basis
Claim 13 recites the limitation "ethyl acetoacetate" and “sodium acetoacetate” in l.1-2 of said claim. There is insufficient antecedent basis for this limitation in the claim.
See claim objection above.
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) 7 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Veech (WO1987003808, of the record).
Veech on p. 16, Table II discloses a composition comprising acetoacetate anion, with sodium anion in solution. Veech on p. 12 states “Thus, as taught herein, therapy (including correction of acidosis, dialysis and/or fluid, electrolyte or nutrient replacement, and the like) in accord with the present invention can be accomplished through the use of any one or more of various anions herein taught in a starting solution wherein the cations are selected from among hydrogen, sodium, potassium, calcium, magnesium, and ammonium.” This indicates that the solution of Table II is formulated to treat acidosis.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
KSR Rationales
The MPEP in section 2143, subsection I gives examples of Rationales for supporting a conclusion of obvious. These rationales are non-exhaustive and include (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results; (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Claim(s) 6-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Veech (cited above, of the record) and in view of Gutierrez (Intensive Care Med. 1996, 22:6-16), Prockop (Journal of the Neurological Sciences, 262, 2007, 122-130), Chan (Case Reports in Medicine, Vol 2009, Article ID 534561, dated 2009), Pham (F1000 Research 2015, 4(F1000 Faculty Rev: 1460), Heinig (Arch Intern Med. Vol. 139, 1979), and Manger (Current Hypertension Reports, 2004, 6:477-484) and as evidenced by Cleveland Clinic (Cleveland Clinic, Metabolic Acidosis, last updated 2022, url=https://my.clevelandclinic.org/health/diseases/24492-metabolic-acidosis, accessed 03/18/2026, and Lactic Acidosis, last updated 06/13/2023, url= https://my.clevelandclinic.org/health/diseases/25066-lactic-acidosis, accessed 03/18/2026).
Claim 6 is drawn to a method of treating an acidosis related disease comprising administering acetoacetate (AcAc).
Claims 8-13 are drawn to embodiments of the claimed method wherein acidosis is lactic acidosis related disease (claim 8), wherein the acidosis related disease is selected from specific conditions (claims 9-12), and wherein the acetoacetate is either ethyl acetoacetate or sodium acetoacetate (claim 13).
Discussion of Veech from the 102 rejection above is incorporated here.
As stated above, Veech contemplates administration of its compositions to treat metabolic acidosis. Veech on p. 3-4, sec. Brief Summary of the Invention contemplates administration of an aqueous solution comprising at least one anion of l-lactate, pyruvate, d-betahydroxybutyrate, and acetoacetate.
Regarding claims 6-8 and 13 Veech on p. 5 contemplates administration of its solution to treat “acidosis, dehydration, blood electrolyte depletion, shock, malnutrition, uremia…”.Veech on p. 13, Table II teaches exemplary compositions comprising acetoacetate and cations in solution. Veech on p. 14 states “Table II describes four classes of physiologic permeant monoanionic metabolite solutions suitable for each of three majors fields of application. The genus class is described in Type A solutions of Table II, where d,l-lactate was previously used, and such improved solutions are suitable for use in treatment of certain forms of metabolic acidosis.”
The instant specification on p. 2 states “As used herein, the term ‘acidosis related diseases’ relates to diseases with acidosis that is to say diseases causing increased acidity in the blood and other body tissues.”
Regarding metabolic acidosis, the Cleveland Clinic states “Metabolic acidosis is a condition in which acids build up in your body.” Regarding lactic acidosis, the Cleveland Clinic state “Lactic acidosis is a type of metabolic acidosis that occurs when lactic acid builds up in your blood.” From these teachings, one of ordinary skill in the art would know that lactic acidosis is a specific type of metabolic acidosis and that the teachings of Veech would embrace methods of treating lactic acidosis.
Regarding claims 9-12, Veech does not explicitly discuss any of the conditions claimed. However, the instant specification on p. 2, l. 31 states “For example, acidosis related diseases are tissular hypoxia like sepsis or septic shock, intoxication to CO (carbon monoxide), hemopathies or some cancers like leukemia, lymphoma or metastatic cancer, intoxication to drug[s] like to metformin, acute liver failure or pheochromocytoma.”
Additionally, each of Gutierrez, Prockop, Chan, Pham, Heinig, and Manger, teach the relation of sepsis, CO intoxication, cancer, metformin intoxication, liver damage, and pheochromocytoma to lactic acidosis or metabolic acidosis.
Gutierrez in sec. Conclusion states “In the setting of sepsis, a high lactate concentration should be interpretated as a marker of disease, one that portends a bad outcome. Increases in blood lactate concentration in septic patients correlate with severity of illness and perhaps indicate severe cellular dysfunction in specific tissue…”.
Prockop on p. 128-129 states “In a recent study, Weaver et al. concluded that [hyperbaric oxygen therapy] is indicated for patients with acute CO poisoning who are ≥ 24 h, or in patients with loss of consciousness, or with higher COHb levels. Close monitoring of the serum pH and lactic acid levels is required, since the anaerobic metabolism in the presence of tissue hypoxia generates lactic acidosis.”
Chan in its abstract states “Lactic acidosis is commonly overserved in clinical situations such as shock and sepsis, as a result of tissue hypoperfusion and hypoxia. Lymphoma and leukemia are among other clinical situations where lactic acidosis has been reported.”
Pham in sec. Drugs causing increased endogenous acid production states “There are still reports of metformin associated lactic acidosis (MALA)…”.
Heinig in its abstract states “Both acute and chronic hepatic insufficiency [liver failure] can result in lactate accumulation and lactic acidosis…”.
Manger on p. 479 states “Pheochromocytoma should be considered in unexplained shock, especially if accompanied by abdominal pain, pulmonary edema, and pronounced mydriasis unreactive to light. Another rare presentation is multi-system organ failure accompanied by severe hypertension or hypotension, encephalopathy, hyperpyrexia, and lactic acidosis.”
The common tether between all of the conditions above is that they present with or include acidosis, lactic or metabolic, in some way. The instant specification also implies that the conditions are not caused by lactic acidosis but rather each share it as a symptom. Therefore, from teachings of Veech, one of ordinary skill in the art could treat the acidosis of the conditions above.
Therefore it would have been prima facie obvious at the time of the effective filing date for one of ordinary skill in the art to have applied the teachings of Veech via the teachings of Gutierrez, Prockop, Chan, Pham, Heinig, and Manger to arrive at the instant claims with a reasonable assumption of success. One of ordinary skill in the art would have found motivation to apply the method of Veech as Veech contemplates efficacy against acidosis which the other references show are symptoms of the conditions above. See KSR rationale A.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUISALBERTO GONZALEZ whose telephone number is (571)272-1154. The examiner can normally be reached M-F 8:30-5:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at (571) 272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624