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 1-12 and 14-21 are pending in the instant application.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-9 and 15-19, in the reply filed on June 17, 2026 is acknowledged. The traversal is on the grounds that groups I-III are drawn to processes of use and are therefore drawn to the same category of invention, and because they share the same technical feature. This is not found persuasive because the shared technical feature is a composition comprising alpha-ketoglutaric acid (α-KG) and 5-hydroxymethyl-2-furfural (5-HMF), which is not a special technical feature as it does not make a contribution over the prior art in view of Groke (US 5,006,551 A). Groke teaches a method of administering a composition comprising α-KG and 5-HMF (claim 1).
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election of ischemia caused by cardiac arrest as the specific disease or condition to be treated and an enhanced hemoglobin-mediated oxygen supply to mitochondria as the benefit to the disease to be treated in the reply filed on June 17, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 10-12, 14, and 20-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on June 17, 2026.
Claims 7, 9, and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on June 17, 2026.
Claims 1-6, 8, and 15-18 are currently under examination as they relate to the elected invention of Group I and elected species of ischemia caused by cardiac arrest.
Priority
This application claims foreign priority to EP21193855.0, filed August 30, 2021, and is a 371 national stage application of PCT/EP2022/74104, filed August 30, 2022.
Drawings
The drawings filed February 28, 2024 have been accepted and entered by the Examiner.
Specification
The following guidelines illustrate the preferred layout for the specification of a utility application. These guidelines are suggested for the applicant’s use.
Arrangement of the Specification
As provided in 37 CFR 1.77(b), the specification of a utility application should include the following sections in order. Each of the lettered items should appear in upper case, without underlining or bold type, as a section heading. If no text follows the section heading, the phrase “Not Applicable” should follow the section heading:
(a) TITLE OF THE INVENTION.
(b) CROSS-REFERENCE TO RELATED APPLICATIONS.
(c) STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT.
(d) THE NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT.
(e) INCORPORATION-BY-REFERENCE OF MATERIAL SUBMITTED ON A READ-ONLY OPTICAL DISC, AS A TEXT FILE OR AN XML FILE VIA THE PATENT ELECTRONIC SYSTEM.
(f) STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINT INVENTOR.
(g) BACKGROUND OF THE INVENTION.
(1) Field of the Invention.
(2) Description of Related Art including information disclosed under 37 CFR 1.97 and 1.98.
(h) BRIEF SUMMARY OF THE INVENTION.
(i) BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING(S).
(j) DETAILED DESCRIPTION OF THE INVENTION.
(k) CLAIM OR CLAIMS (commencing on a separate sheet).
(l) ABSTRACT OF THE DISCLOSURE (commencing on a separate sheet).
(m) SEQUENCE LISTING. (See MPEP § 2422.03 and 37 CFR 1.821 - 1.825). A “Sequence Listing” is required on paper if the application discloses a nucleotide or amino acid sequence as defined in 37 CFR 1.821(a) and if the required “Sequence Listing” is not submitted as an electronic document either on read-only optical disc or as a text file via the patent electronic system.
The disclosure is objected to because the specification does not provide any section headings.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
112(a) – Scope of Enablement
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, 3-6, 8, and 15 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 a method of treating a disease or condition that benefits from an enhanced hemoglobin-mediated oxygen delivery, comprising administering to a subject a pharmaceutical composition comprising alpha-ketoglutaric acid (α-KG) and 5-hydroxymethylfurfural (5-HMF), does not reasonably provide enablement for a method of preventing the same diseases and 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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention is drawn to the use of compounds in claim 1 to treat inflammation and immune responses in a subject infected with a virus.
The relative skill of those in the art is high, generally that of a M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
As evident of the state of the art of treating and preventing hypoxia and ischemia, the examiner cites Samuel (“Hypoxemia and Hypoxia”). Samuel teaches hypoxia can be caused by V/Q mismatch, in turn caused by pneumonia, heart failure, and atelectasis; cirrhosis; anemia; and cyanide poisoning ((p. 391, right, paras. 3-7). Samuel notes that atelectasis and pneumonia are more common in patients who are elderly obese, or have neurologic disease (p. 392, left, para. 2).
As evident of the state of the art of treating and preventing ischemia, the examiner cites Ekker et al. (Stroke 2023;54:439–447). Ekker teaches risk factors for ischemic stroke and corresponding cerebral ischemia (see p. 440, right, para. 3 for link between ischemic stroke and cerebral ischemia) include diverse causes such as carotid artery dissection, drug use, pregnancy, HIV, acute systemic infection, hypotension, and more (p. 442, Table 2).
As the prior art indicates, the risk factors leading to hypoxia, hypoxemia, and ischemia, diseases or conditions recited as benefiting from increased hemoglobin-mediated oxygen delivery (see instant claim 6), are unpredictable and hence impossible to fully prevent. These factors include both acute events, such as infection and cyanide poisoning, and chronic conditions and lifestyle factors such as obesity and drug use. Expanding beyond the scope of hypoxia, hypoxemia, and ischemia, it would be impossible to fully predict or prevent all diseases and conditions benefiting from increased hemoglobin-mediated oxygen delivery, given the range of acute and chronic causes noted above.
The breadth of the claims
Claims 1, 3-6, 8, and 15 are very broad in terms of the type of diseases being treated: all diseases and conditions benefiting from increased hemoglobin-mediated oxygen delivery are claimed to be treated and prevented by administering a composition comprising α-KG and 5-HMF.
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides data showing that that the combined administration of 5-HMFand α-KG increased hemoglobin–oxygen affinity in human whole blood (p. 27, para. 5). Although this provides reasonable enablement for treating diseases or conditions that benefit from an enhanced hemoglobin-mediated oxygen delivery or from an enhanced hemoglobin-mediated oxygen supply to mitochondria (see definitions of such diseases in p. 6, paras. 3-4), the same cannot be said about preventing said diseases. As noted supra, such diseases, including hypoxia, hypoxemia, and ischemia, have a range of lifestyle factors and risks that cannot be adequately or reasonably predicted, let alone prevented solely through administration of a composition comprising α-KG and 5-HMF.
4. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that administration of a composition comprising α-KG and 5-HMF could predictably prevent diseases or conditions that benefit from an enhanced hemoglobin-mediated oxygen delivery or from an enhanced hemoglobin-mediated oxygen supply to mitochondria.
Determining if a particular compound will prevent any particular disease state would require formulation into a dosage form, and subjecting into clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicant.
Accordingly, the inventions of claims 1, 3-6, 8, and 15 do not comply with the scope of enablement requirement of 35 U.S.C 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation with no assurance of success.
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.
Claims 1-6 and 15-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Matzi et al. (European Journal of Cardio-thoracic Surgery 32.5: 776-782 (2007), cited in the IDS dated May 28, 2024), as evidenced by CAS Registry No. 67-47-0.
Matzi teaches administering a combination of 7.2 g α-ketoglutaric acid (α-KG) and 720 mg 5-hydroxymethylfurfural (5-HMF)/day daily to patients admitted for lung resection surgery for 10 days reduces oxidative stress markers including carbonyl proteins (CPs) and isoprostanes (IPs) (abstract). Matzi teaches IPs and CPs are biomarkers of oxidative damage during lung ischemia and reperfusion (p. 777, left, para. 1) and that the administration of α-KG and 5-HMF reduces these biomarkers (p. 782, left, para. 1, lines 5-7 and 13-16).
(As evidenced by CAS Registry No. 67-47-0, 5-hydroxymethylfurfural is also known as 5-hydroxymethyl-2-furfural (p. 1; 5-(hydroxymethyl)-2-furfural 5th line of “Other Names”; 5-hydroxymethylfurfural line 13 of same section)).
Regarding claims 1, 5-6 and 15, the daily administration of a composition comprising α-KG and 5-HMF to patients with oxidative damage caused by lung ischemia reads on a method of treating or preventing a disease or condition that benefits from an enhanced hemoglobin-mediated oxygen delivery, comprising administering to a subject a pharmaceutical composition comprising α-KG and 5-HMF. It also reads on a method of treating or preventing a disease or condition that benefits from an enhanced hemoglobin-mediated oxygen supply to mitochondria. (Although the prior art does not explicitly mention ischemia is a disease or condition that benefits from an enhanced hemoglobin-mediated oxygen delivery, it reads on a disease recited as such in instant claim 6. Similarly, although the prior art does not explicitly teach ischemia as a disease or condition that benefits from an enhanced hemoglobin-mediated oxygen supply to mitochondria, as per the instant specification, such diseases or conditions “can preferably be selected from one or more of the diseases or conditions disclosed in connection with the first aspect of the present invention” (p. 21, para. 3); i.e., diseases or conditions that include ischemia (see p. 13 of instant specification for such diseases or conditions in the first aspect). Thus, ischemia reads on a “disease or condition that benefits from an enhanced hemoglobin-mediated oxygen supply to mitochondria”.)
Regarding claim 2, the prior art is silent regarding “enhancing hemoglobin-mediated oxygen supply". However: “enhancing hemoglobin-mediated oxygen supply" will inevitably flow from the teachings of the prior art (see above rejection), since the composition comprising α-KG and 5-HMF is being administered to the same population (a subject). In other words, products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances.
In other words, even though the prior art is silent regarding “enhancing hemoglobin-mediated oxygen supply", by practicing the method taught by the prior art: administering a composition comprising α-KG and 5-HMF to a subject, one will also be “enhancing hemoglobin-mediated oxygen supply", even though the prior art was not aware of it.
Apparently, Applicant has discovered a new property or advantage (“enhancing hemoglobin-mediated oxygen supply”) of the method taught by the prior art (administering a composition comprising α-KG and 5-HMF to a subject).
MPEP 2112 I states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Regarding claims 3 and 16, the administration of 7.2 g α-KG and 720 mg 5-HMF is a mass ratio of 10:1, which reads on wherein the ratio is between 1:1 and 100:1.
Regarding claims 4 and 17, assuming a patient mass of 70 kg, a dosage of 7.2 g α-KG yields a dosage of 102.9 mg/kg. A dosage of 720 mg 5-HMF to the same subject yields a dosage of 10.29 mg/kg. These both read on the instantly claimed dosages.
Therefore, the reference anticipates the instantly claimed invention.
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.
Claims 1-6, 8, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Matzi et al. (European Journal of Cardio-thoracic Surgery 32.5: 776-782 (2007), cited in the IDS dated May 28, 2024), as evidenced by CAS Registry No. 67-47-0, in view of Jentzer (BioMed Research International, 2015, 314796, 14 pages, 2015).
The teachings of Matzi as evidenced by CAS Registry No. 67-47-0 are set forth above and applied as before. In summary, Matzi teaches administering a combination of 7.2 g α-KG and 720 mg 5-HMF/day daily to patients admitted for lung resection surgery reduces oxidative stress markers including carbonyl proteins (CPs) and isoprostanes (IPs) (abstract). Matzi teaches IPs and CPs are biomarkers of oxidative stress during lung ischemia and reperfusion (p. 777, left, para. 1), and that the administration of α-KG and 5-HMF reduces these biomarkers (p. 782, left, para. 1, lines 5-7 and 13-16). Matzi notes that surgical trauma may increase the formation of reactive oxygen and nitrogen species (RONS) in tissues including lung and heart cells (p. 781, right, para. 1), and that elevated levels of CPs and IPs are also associated with the metabolism of RONS and are a sign of oxidative stress (p. 781, right, para. 2).
Matzi does not teach the administration of α-KG and 5-HMF to treat patients suffering from ischemia caused by cardiac arrest.
Jentzer teaches ischemia is a common complication after cardiac arrest (abstract, lines 5-7; also p. 4, left, para. 1). Jentzer also teaches that overproduction of toxic reactive oxygen species after transient ischemia leads to a wave of cellular injury (p. 4, right, para. 1). Furthermore, Jentzer teaches mitochondrial disfunction can result from the cellular effects of ischemia reperfusion injury (IRI; abbreviation defined p. 1, last line of left col. into first line of right col.) and oxidative stress caused by elevated reactive oxygen species levels (p. 5, right, para 1.).
Regarding claim 8, it would have been obvious to one of ordinary skill in the art before the filing of the instant invention to administer a composition comprising α-KG and 5-HMF to treat ischemia caused by cardiac arrest because Matzi teaches the administration of such a composition reduces oxidative stress in patients with ischemia from lung resection surgery, and because Jentzer teaches ischemia caused by cardiac arrest leads to overproduction of toxic reactive oxygen species and associated oxidative stress. One would have been motivated and had a reasonable expectation of success to administer a composition comprising α-KG and 5-HMF to treat oxidative stress in patients with ischemia caused by cardiac arrest, since the prior art teaches both ischemia caused by surgery and ischemia caused by cardiac arrest lead to oxidative stress caused by reactive oxygen species and because the administration of a composition comprising 5-HMF and α-KG treats oxidative stress in ischemia caused by surgery.
In other words, because a composition comprising 5-HMF and α-KG treats oxidative stress caused by one type of ischemia, one would be motivated to apply the same method to treat a different type of ischemia and had a reasonable expectation of success in doing so.
Conclusion
Claims 1-6, 8, and 15-18 are rejected.
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Schwarz et al. (WO 2012/139148 A1, cited in the IDS dated July 27, 2026) teaches an antioxidant composition comprising a combination of α-KG and 5-HMF (claim 7). Schwarz also teaches a method of treating a graft before transplantation with said antioxidant composition (claim 15).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OLIVER D. HEES whose telephone number is (571)272-9840. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, AMY L. CLARK can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/O.D.H./Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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