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 .
Election/Restrictions
Applicant’s election without traverse of methemoglobin as the species in the reply filed on 10/16/25 is acknowledged.
Applicant did not identify the claims readable on the elected species, see 9/18/25 Restriction Requirement, page 4. However, for compact prosecution all claims are examined.
Claim Status
Claims 1-6 are pending.
Claims 1-6 are rejected.
Priority
The instant application, filed 02/24/2023 is a National Stage entry of PCT/JP2021/031458 , International Filing Date: 08/27/2021
claims foreign priority to 2020-144044, filed 08/28/2020.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 12/26/24, 1/6/25 and 10/3/25 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because the writing in Figures 5 and 6 is blurred and unreadable. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed. This is because the title includes “endoplasmic reticulum” which appears unrelated to the administered active ingredients and may be due to an inaccurate translation.
The following title is suggested: Methods for treating cyanide, hydrogen sulfide and azide poisoning.
Claim Rejections - 35 USC § 112
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 1-6 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 a poisoning selected from the group of cyanide poisoning, hydrogen sulfide poisoning, and azide poisoning, when administering the claimed heme protein medicament five and ten minutes after such poisoning takes place, and for preventing or reducing symptoms of a poisoning selected from the group of cyanide poisoning, hydrogen sulfide poisoning, and azide poisoning, when administering the claimed heme protein medicament five minutes before such poisoning takes place, does not reasonably provide enablement for all administering for treating or for preventing when the time between the poisoning and the later administering exceeds forty minutes for cyanide poisoning, twenty minutes for hydrogen sulfide poisoning, and sixty minutes for azide poisoning, this based on the data of Figures 16, 17 and 14, respectively, and does not reasonably provide enablement for all administering for treating or for preventing when the time between the poisoning and the earlier administering exceeds one day, this based on the expected in vivo recycling of the administered methemoglobin of the medicament to hemoglobin, see Jay Umbreit, Am Jl. Of Hematology, 82:134-144 (2007), copy provided (but also depending on the administered methemoglobin dose). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The analysis is as follows.
(A) Breadth of Claims: claim 1 is directed to method of treating or preventing cyanide poisoning, hydrogen sulfide poisoning and azide poisoning, the method comprising administering a medicament or pharmaceutical composition comprising as an active ingredient(s) one or more of a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions. Claim 2 narrows to methemoglobin, and other claims further limit by what type of composition is administered, claims 3 and 4, and specifically to treating or preventing, claims 5 and 6.
(B) The nature of the invention: The invention is directed to address poisoning by cyanide, hydrogen sulfide and azide (either together or separately).
(C) The state of the prior art: Methemoglobin is known in the art to prevent such poisoning when administered shortly before a toxic dose of cyanide is given to rodents in a laboratory setting, so a form of preventing, see Smith and Gosselin, Toxicology and Applied Pharmacology, 8, 159-172 (1966), provided in 1/6/25 IDS (“SG”), and to treat cyanide poisoning based on rodent testing in a laboratory setting, see Ten Eyck et al., Clinical Toxicology, 21(3), 343-358 (1983-84), provided in 12/26/24 IDS (“TE”). SG also teaches that it was known in the art that methemoglobin affords protection against all three of cyanide, sulfide and azide ions.
(D) The level of one of ordinary skill: This is high.
(E) The level of predictability in the art: The level of predictability is reasonably high given the knowledge in the art regarding binding of cyanide, sulfide and azide ions to methemoglobin and other molecules, and the progression of toxicity, which for these toxins at high doses can quickly lead to death, see SG and TE.
(F) The amount of direction provided by the inventor and (G) The existence of working examples: The rodent experiments with the toxins involved administering an “antidote”, e.g., methemoglobin in a liposome preparation, such as five minutes before administering one of the claimed toxins, for “preventing”, and administering such methemoglobin preparation 5 and 10 minutes after administering one of the claimed toxins, for “treating”. See pages 26-34.
Additionally, there is no substantive meaningful teaching, disclosure or examples of the types and ranges of claim 1 “a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions” that can be used effectively in the method, whether for administering shortly before or after toxin exposure, or for longer time periods between administering and toxin exposure.
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Owing to factors above, the quantity of experimentation needed is expected to be great. This is particularly the case because preventing a disease or condition can include administering an agent, such as a vaccine, months or years before a potential exposure to a pathogen. Here, given the speed of death after exposure to these toxins when exposed in sufficient (but relatively small) amounts is rapid. Also methemoglobin in excessive amounts itself causes dysfunction, and administering methemoglobin months or years in advance of an exposure to these toxins likely would have not be effective because such methemoglobin would be processed by methemoglobin reduction mechanisms long before such exposure, see page 135 left column and also regarding inflammation and other problems with excessive methemoglobin, Jay Umbreit, Am Jl. Of Hematology, 82:134-144 (2007), copy provided.
No clear guidance is provided as how to prevent and/or treat by administering methemoglobin or other claimed agent days, weeks, months or years before or after an exposure to one of the claimed toxins. The basic biology and chemistry argues strongly against a long interval between administering and toxin exposure to have any effect. As such a huge amount of experiments would need to be conducted, and the likelihood of success for intervals between toxic intake and administering that exceed minutes or an hours is very low.
The skilled practitioner would first turn to the instant description for guidance in using the claimed invention. However, the description lacks clear evidence that Applicant has demonstrated how to practice the invention other than for administering shortly before or shortly after toxin exposure. As such, the skilled practitioner would turn to the prior art for such guidance, however the prior art does not discuss to any meaningful extent how to achieve what is claimed for longer intervals between administering and exposure. Finally, said practitioner would turn to trial and error to try to achieve what is unlikely able to be achieved. This amounts to undue experimentation in view of the teachings of the specification.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here.
Claims 1 and 3-6 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification provides is no substantive nor meaningful teaching, disclosure or examples of the types and ranges of claim 1’s “a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions” that can be used effectively in the method, whether for administering shortly before or after toxin exposure, or for longer time periods between administering and toxin exposure.
There are insufficient species (i.e., none other than methemoglobin, note that derivative is mentioned 6 times without examples or features) and insufficient teachings and disclosure of structure/function, or other necessary characteristics, to demonstrate possession of the potentially large genus of these heme proteins, substances containing such, and heme derivatives that fall within the claimed “capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions.” Nor have these reasonably been demonstrated to be effective for what is claimed, including any time between administering and exposure to toxin.
Accordingly, applicant is not in possession of what is claimed in claims 1 and 3-6, and as such is rejected under this section.
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.
Claim(s) 1, 2, and 6 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Smith and Gosselin, Toxicology and Applied Pharmacology, 8, 159-172 (1966), provided in 1/6/25 IDS (“SG”).
Claim 1 as interpreted under this rejection includes a method for preventing a poisoning selected from the group consisting of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning, the method comprising administering a medicament or pharmaceutical composition comprising as an active ingredient(s) one or more of a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions.
Claim 2 narrows the heme protein of claim 1 to methemoglobin.
Claim 6 depends from claim 1 and limits claim 1 to the method of preventing, as interpreted here, one of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
SG clearly teaches that methemoglobin is recognized to protect, as demonstrated in mice, against the lethality of subsequent challenge by sodium azide and sodium or hydrogen sulfide, and that “methemoglobin is presently recognized to afford protection against three toxic anions in vivo, namely cyanide, sulfide and azide,” Abstract on page 159. See also the experiments demonstrating effectiveness, including Table 1, Fig. 3, Table 5 and associated text.
Claims 1, 2 and 6 accordingly are anticipated by SG.
Claim(s) 1, 2 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ten Eyck et al., Clinical Toxicology, 21(3), 343-358 (1983-84), provided in 12/26/24 IDS (“TE”).
Claim 1 as interpreted under this rejection includes a method for preventing a poisoning selected from the group consisting of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning, the method comprising administering a medicament or pharmaceutical composition comprising as an active ingredient(s) one or more of a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions.
Claim 2 narrows the heme protein of claim 1 to methemoglobin.
Claim 5 depends from claim 1 and limits claim 1 to the method of treating, as interpreted here, one of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
TE teaches and exemplifies that methemoglobin treats cyanide poisoning in rats when administered shortly after cyanide dosing, Materials and Methods, and also Results, pages 345-350, notably Table 3 on page 349.
Claims 1, 2 and 5 accordingly are anticipated by TE.
Claim(s) 1-5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US 20190290739, published 9/26/19, inventors Rose et al. (“Rose”).
Claim 1 as interpreted under this rejection includes a method for preventing a poisoning selected from the group consisting of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning, the method comprising administering a medicament or pharmaceutical composition comprising as an active ingredient(s) one or more of a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions.
Claim 2 narrows the heme protein of claim 1 to methemoglobin.
Claim 3 depends from claim 1 and as reasonably interpreted what is administered in claim 1 is a methemoglobin-containing erythrocyte or a methemoglobin-containing capsule.
Claim 4 depends from claim 3 and as reasonably interpreted further narrows the claim 3 to “the capsule comprises at least one selected from the group consisting of a liposome, a polymersome, and a polymer thin film.
Claim 5 depends from claim 1 and limits claim 1 to the method of treating, as interpreted here, one of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
Rose teaches and claims treating cyanide poisoning, claim 34 stating, “A method of treating cyanide poisoning in a subject, comprising: selecting a subject with cyanide poisoning; and administering to the subject a therapeutically effective amount of a composition comprising a natural or an artificial oxygen carrier, wherein the oxygen carrier is in its oxidized form,” claim 37 stating, “The method of claim 34, wherein the oxygen carrier is a natural oxygen carrier comprising a globin protein,” claim 38 stating, “The method of claim 37, wherein the globin protein comprises hemoglobin or myoglobin,” and paragraph 60 stating, “Methemoglobin: The oxidized form of hemoglobin in which the iron in the heme component has been oxidized from the ferrous (+2) to the ferric (+3) state. This renders the hemoglobin molecule incapable of effectively transporting and releasing oxygen to the tissues. Normally, there is about 1% of total hemoglobin in the methemoglobin form.” Similar to claim 34, paragraph 10 states, “Also provided is a method of treating cyanide poisoning in a subject by selecting a subject with cyanide poisoning and administering to the subject a therapeutically effective amount of a composition that includes a natural or an artificial oxygen carrier, wherein the oxygen carrier is in its oxidized form.” See also paragraphs 103-104.
Claims 1, 2 and 5 accordingly are anticipated by Rose.
Because Rose also teaches in its section for treating cyanide poisoning, using a liposome-encapsulated globin protein, such as a liposome-encapsulated hemoglobin or a liposome-encapsulated myoglobin, paragraph 118, so that this is at once envisaged, Rose anticipates claims 4 and 5.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-6 are rejected under 35 U.S.C. 103 as being unpatentable over US 20190290739, published 9/26/19, inventors Rose et al. (“Rose”) in view of Smith and Gosselin, Toxicology and Applied Pharmacology, 8, 159-172 (1966), provided in 1/6/25 IDS (“SG”).
Claim 1 as interpreted under this rejection includes a method for preventing a poisoning selected from the group consisting of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning, the method comprising administering a medicament or pharmaceutical composition comprising as an active ingredient(s) one or more of a) a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, a substance containing a heme protein capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions, and a heme derivative capable of binding to cyanide ions, hydrogen sulfide ions, and azide ions.
Claim 2 narrows the heme protein of claim 1 to methemoglobin.
Claim 3 depends from claim 1 and as reasonably interpreted what is administered in claim 1 is a methemoglobin-containing erythrocyte or a methemoglobin-containing capsule.
Claim 4 depends from claim 3 and as reasonably interpreted further narrows the claim 3 to “the capsule comprises at least one selected from the group consisting of a liposome, a polymersome, and a polymer thin film.
Claim 5 depends from claim 1 and limits claim 1 to the method of treating, as interpreted here, one of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
Claim 6 depends from claim 1 and limits claim 1 to the method of preventing, as interpreted here, one of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
Rose teaches and claims treating cyanide poisoning, claim 34 stating, “A method of treating cyanide poisoning in a subject, comprising: selecting a subject with cyanide poisoning; and administering to the subject a therapeutically effective amount of a composition comprising a natural or an artificial oxygen carrier, wherein the oxygen carrier is in its oxidized form,” claim 37 stating, “The method of claim 34, wherein the oxygen carrier is a natural oxygen carrier comprising a globin protein,” claim 38 stating, “The method of claim 37, wherein the globin protein comprises hemoglobin or myoglobin,” and paragraph 60 stating, “Methemoglobin: The oxidized form of hemoglobin in which the iron in the heme component has been oxidized from the ferrous (+2) to the ferric (+3) state. This renders the hemoglobin molecule incapable of effectively transporting and releasing oxygen to the tissues. Normally, there is about 1% of total hemoglobin in the methemoglobin form.” Similar to claim 34, paragraph 10 states, “Also provided is a method of treating cyanide poisoning in a subject by selecting a subject with cyanide poisoning and administering to the subject a therapeutically effective amount of a composition that includes a natural or an artificial oxygen carrier, wherein the oxygen carrier is in its oxidized form.” See also paragraphs 103-104.
Based on the above, a person of ordinary skill in the art would understand that methemoglobin is among the claim 37 hemoglobins administered in claim 34, the latter requiring that the oxygen carrier is in its oxidized form.
Although Rose clearly teaches the method of claim 1 for treating cyanide poisoning (see 35 USC 102 rejection above), Rose does not teach preventing cyanide poisoning, nor treating or preventing hydrogen sulfide poisoning nor azide poisoning as encompassed by claim 1 and when the elected species methemoglobin is considered.
The level of ordinary skill in the art is high.
SG clearly teaches that methemoglobin is recognized to protect, as demonstrated in mice, against the lethality of subsequent challenge by sodium azide and sodium or hydrogen sulfide, and that “methemoglobin is presently recognized to afford protection against three toxic anions in vivo, namely cyanide, sulfide and azide,” Abstract on page 159. See also the experiments demonstrating effectiveness, including Table 1, Fig. 3, Table 5 and associated text. The protection is achieved in the examples by administering methemoglobin shortly before administering the toxin.
Based on the teachings and examples in SG, when considering the treatment approaches in Rose for treating cyanide poisoning, one of ordinary skill in the art would have reasonably concluded that the same treatment approaches taught in Rose, including using liposomes, would have been effective to treat hydrogen sulfide poisoning and azide poisoning, and also, based on SG, at least under particular and specific conditions, to prevent all of cyanide poisoning, hydrogen sulfide poisoning and azide poisoning.
The rationale is applying a known technique to a known method ready for improvement or expansion to yield predictable results. Rose taught a "base" method for treating cyanide poisoning upon which the claimed invention can be seen as an "improvement”, expanding the scope of practice to include preventing cyanide poisoning and also treating and preventing hydrogen sulfide poisoning and azide poisoning. SG teaches known techniques and knowledge, regarding methemoglobin recognized to afford protection against cyanide, sulfide and azide toxic anions, that is applicable to the Rose method to expand its usage. Given the teachings and examples of Rose and SG, one of ordinary skill in the art would have recognized that applying the known technique and knowledge of SG would have yielded predictable results and resulted in improved and expanded methods to expand Rose’s methods to also prevent, under particular and specific conditions, cyanide poisoning, and also to treat hydrogen sulfide poisoning and azide poisoning, and to prevent these under particular and specific conditions. There would have been a reasonable expectation of success given the strong teachings of SG.
Accordingly, claims 1-6 would have been obvious.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Examiner, Art Unit 1658