DETAILED ACTION
This office action is in response to applicant’s filing dated February 17, 2026.
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 Claims
Claims 1 and 6-13 are pending in the instant application. Acknowledgement is made of Applicant's amendments filed February 17, 2026. Acknowledgement is made of Applicant's amendment of claims 1, 6, 7, and 11-13; and cancelation of claims 2-5.
Applicants elected with traverse (i) (1S, 4R, 5R, 7S) -3,4-dibenzyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1] octane-7-carboxylic L-lysine Salt (MT8) as the elected compound of Formula (I) species and (ii) sepsis as the elected inflammatory disease species in the reply filed on August 4, 2025. The requirement is still deemed proper. Claims 8-10 and 12 remain withdrawn.
Claims 1, 6, 7, 11, and 13 are presently under examination as they relate to the elected species: (1S, 4R, 5R, 7S) -3,4-dibenzyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1] octane-7-carboxylic L-lysine Salt (MT8) and (ii) sepsis.
Priority
The present application is a 371 of PCT/IB2021/053062 filed on April 14, 2021, which claims benefit of foreign priority to ITALY 102020000008125 filed on April 16, 2020.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Withdrawn Objections and/or Rejections
Drawings
Acknowledgement is made of the drawings received on February 17, 2026. These drawings are accepted.
Claim Objections
The objection to claims 1-7, 11, and 13 has been rendered moot in view of the claim amendment. Thus, the objection has been withdrawn.
Claim Rejections - 35 USC § 112(d)
The rejection of claim 5 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends has been rendered moot in view of the cancelation of claim 5. Thus, the rejection has been withdrawn.
New Objections and/or Rejections
Necessitated by Claim Amendment
Claim Rejections - 35 USC § 112(b)
Indefinite
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.
Claim 1, 7, 11, and 13 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 1 recites the phrase “said compound of formula (I) comprising: (IA) or (IB)…”
Compound of formula (I) appears to be directed to a compound structure; however the open language “comprising” suggests that a compound of formula (I) encompasses additional components. It is not clear if applicant intends for the phrase to encompass the specific compounds or for the phrase to encompass a composition. In the interest of compact prosecution, the phrase has been construed as said compound of formula (I) is selected from (IA) or (IB).
Dependent claims 7, 11, and 13 do not clarify the ambiguity of claim 1. Thus, the rejection also applies to claims 7, 11, and 13.
Modified Objections and/or Rejections
Modifications Necessitated by Claim Amendment
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 1-7, 11, and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. This is an 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:
1. The nature of the invention
Claims 1, 6, 7, 11, and 13 recite a method of treating inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response, said method comprising administering to a subject in need thereof a compound of formula (I) as an activator of Adenosine Deaminase Acting on RNA 1 (ADAR1) , said compound of formula (I) comprising: (IA or IB):
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2. The relative skill of those in the art
The relative skill of those in the art is high, generally that of an 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.
3. The state and predictability of the art
As illustrative of the state of the art regarding the treatment of inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response, the Examiner refers to Jarczak et al (Int. J. Mol. Sci., 2022; 23:11740 pp 1-30).
Jarczak teaches the human innate and adaptive immune systems consist of effector cells producing cytokines (interleukins, interferons, chemokines, and numerous other mediators); usually, a fragile equilibrium of pro- and anti-inflammation effects is maintained by complex regulatory mechanisms; disturbances of this homeostasis can lead to intricate chain reactions resulting in a massive release of cytokines; this may result in a drastic self-reinforcement of various feedback mechanisms, which can ultimately lead to systemic damage, multi-organ failure, or death; not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies; due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce (abstract). Jarczak teaches to date, there is no valid definition for the term CS (cytokine storm); it is usually understood to mean an overwhelming immune response characterized by the release of cytokines, including interleukins, interferons, chemokines, and other mediators (page 1, last paragraph); and CS means that the dynamics and quantity of systemically released cytokines cause serious damage in the host organism; however, distinguishing between an appropriate and a pathologically dysregulated inflammatory response in critical illness is difficult or impossible (page 2, 1st paragraph). Jarczak teaches since most of the mediators involved in the CS exhibit pleiotropic downstream effects and, in addition, are often interdependent in their biological activity, an extremely complex dynamic arises; the interaction of the mediators and the signaling pathways triggered by them are neither linear nor uniform; moreover, their quantitative values may indicate the severity of the reactions, but not necessarily pathogenesis, clinical features, and prognosis; this complex interplay highlights the limitations of intervening in the acute inflammatory response based on single mediators and at undifferentiated time points (page 2, 1st paragraph). Jarczak teaches depending on the underlying causes and therapeutic measures, cases of CS differ from each other both in onset and duration (page 4, last paragraph).
In regards to the elected inflammatory disease species sepsis, Jarczak teaches the complexity of the sepsis syndrome, together with the multi-level inter-organ cross talk, entails that even after more than three decades of research, there is no specific cure—and there probably never will be; even in precision or personalized medicine, where treatments are targeted at pre-specified conditions or individual patient requirements, no ground-breaking success has been achieved to date; an example of this is the approach known as theranostics, where selected biomarkers are used to choose a specific therapy and simultaneously measure the response to this treatment; however, it is likely that there is a right time for each element of the immune response to be enhanced or attenuated during the defense against severe infections; initially, when the pathogen load is high, the demands on the immune system are quite different from those at a later stage, when the pathogens are largely contained by effective anti-infective measures; in other words, applying the right therapeutic approach at the wrong time can potentially worsen clinical outcomes; furthermore, if anti-inflammatory interventions are only effective in certain subgroups of patients, demonstrating their efficacy in heterogeneous populations recruited in most clinical sepsis trials remains extremely difficult (page 5, 3rd paragraph).
A search of the prior art revealed that the compounds of formula I are known to be useful for treating ischemia reperfusion injury disorders. However, there is no teachings that compounds of the instantly claimed structure are useful for treating any of the various pathogen related disorders, congenital diseases or immunomodulatory therapies encompassed by inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response.
4. The breadth of the claims
The breadth of the claims is not commensurate in scope with the disclosure.
The scope of the claims are narrow in terms of the compounds claimed to be useful for in the claimed method. However, the scope of diseases encompassed by inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response is extremely broad.
5. The amount of direction or guidance provided and the presence or absence of working examples
MPEP 2164.03 states: “The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements. In re Vickers, 141 F.2d 522, 526-27, 61 USPQ 122, 127 (CCPA 1944); In re Cook, 439 F.2d 730, 734, 169 USPQ 298, 301 (CCPA 1971). However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In re Soll, 97 F.2d 623, 624, 38 USPQ 189, 191 (CCPA 1938). In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991). This is because it is not obvious from the disclosure of one species, what other species will work”.
The specification only discloses the effect of MT8 on the production of IL-1β, TNF-α, and IL-6 in human monocytes and human dendritic cells stimulated with LPS (see Experiment 1, page 17); the effect of MT8 on activation of the homodimeric complex ADAR1 (see Experiment 2, page18); effect of MT8 expression of miR-101 in an in vitro model of inflammation (see example 3, page 18); and effect of MT8 on miR-101 expression levels following ADAR1 knock-down. The specification and the prior art appears to be silent on a nexus between the ADAR1 activity of these compounds and their efficacy for treating any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis in vivo.
That is, where physiological activity is concerned (i.e., the claimed method of treatment), one skilled in the art reasonably would not and properly should not accept in vitro results as support for in vivo activity. Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1216-1217, 18 USPQ2d 1016, 1030 (Fed. Cir.), cert. denied, 502 U.S. 856 (1991) (“we hold that the district court erred in accepting the in vitro data as support for claims containing what has been found to be an in vivo limitation”). Therefore, to enable one skilled in the art to use a method of treatment in vivo based solely on in vitro testing some evidence correlating in vivo results to in vitro testing at the pertinent time is required. See In re Brana, 51 F.3d 1560, 1565 USPQ2d 1437, 1442 (Fed. Cir. 1995) (to enable one skilled in the art to use a clinical method based on preclinical testing, the preclinical testing must be shown to be statistically significant) and Cross v. Iizuka, 753 F.2d 1040, 1050-1051, 224 USPQ 739, 747-748 (Fed. Cir. 1985) (preclinical testing activity must at least reasonably correlate to clinical activity to establish utility).
As such, if there is no correlation, then the in vitro ADAR1 activity examples do not constitute working examples.
While it is understood that the absence of working examples should never be the sole reason for rejecting a claim as being broader than an enabling disclosure, the criticality of working examples in an unpredictable art, such as the treatment of any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including sepsis, and in particular with novel untested compounds, is required for practice of the claimed invention.
6. The quantity of experimentation necessary
As discussed above (see: 3. the state and predictability of the art), there is a high unpredictability in the art of treating any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis; the instantly claimed compounds are only known to for use in ischemia reperfusion injury, as such no biological/pharmacological data is known to be associated with these structures and any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response. Based on this and in the absence of experimental evidence commensurate in scope with the claims (see: 5. The amount of direction or guidance and the presence or absence of working examples above), the skilled in the art will not accept that a compound of formula I, will be effective in treating any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis as inferred by the claims and contemplated by the specification because neither the prior art nor the specification disclose a single compound of formula I that correlates with the treatment of any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis.
So, determining which compound of formula I, if any, will be effective in treating any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis, will require first require testing new synthetic pathways for the thousands of compounds that were not specifically disclosed in the specification, assaying these compounds in an assay that correlates with the treatment of any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis, and then further determine their efficacy in a validated animal model.
All this is undue experimentation given the limited guidance and direction provided by Applicants.
7. Conclusion
Accordingly, the inventions of claims 1, 6, 7, 11, and 13 do not comply with the enablement requirement of 35 U.S.C 112, first paragraph, 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.
Response to Arguments
Applicant argues:
According to prior art, the LPS-stimulated immune cell model is commonly used model and is considered a “gold standard” in cytokine storm research, capable of simulating the activation of key pathways in systemic inflammatory responses. Further, ADAR1 activation can inhibit miR-101, and miR-101 has been proven to directly regulate the expression of pro-inflammatory cytokines. Thus, experimental protocols and experimental data provided in the application provide evidence that compounds of formula (IA) or (IB) are able to induce a decrease in the release of pro-inflammatory cytokines by way of a high activation of ADAR1 (homodimerization), leading to a significant reduction in the expression of miR-101; and, reduction of the systemic production of cytokines, upstream of IL-6 in the functional cascade and therefore acting in reduction of the effects deriving from the "cytokine storm" or CSS. The discovery that molecules of formula (IA) or (IB) act through the mechanism of ADAR1 activation enables the therapeutic treatment of a new subgroup of diseases characterized by cytokine storms and/or uncontrolled immune responses.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, the state of the art of treatment of inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response is highly unpredictable. As set forth above, massive release of cytokines (“cytokine storm”) can ultimately lead to systemic damage, multi-organ failure, or death; not only pathogens can initiate such disturbances, but also congenital diseases or immunomodulatory therapies; due to the complex and diverse interactions within the innate and adaptive immune systems, the understanding of this important clinical syndrome is incomplete to date and effective therapeutic approaches remain scarce. Moreover, as set forth above, Jarczak teaches to date, there is no valid definition for the term CS (cytokine storm); it is usually understood to mean an overwhelming immune response characterized by the release of cytokines, including interleukins, interferons, chemokines, and other mediators; and CS means that the dynamics and quantity of systemically released cytokines cause serious damage in the host organism; however, distinguishing between an appropriate and a pathologically dysregulated inflammatory response in critical illness is difficult or impossible. The art clearly establishes that the term cytokine storm does not have a valid definition and distinguishing between an appropriate and a pathologically dysregulated inflammatory response in critical illness is difficult or impossible. As set forth above, the specification and the prior art appears to be silent on a nexus between the ADAR1 activity of these compounds and their efficacy for treating any inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response including the elected sepsis in vivo. Thus, as set forth above, the in vitro ADAR1 activity examples do not constitute working examples.
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.
Claims 1-7 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Guarna et al (US 2015/0080388 A1).
Regarding claims 1-6, Guarna teaches a method for treating ischemia-reperfusion related pathologies comprising administering to a patient in need thereof an effective amount of a compound of formula (I) (claim 22):
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; wherein R1 is PhCH2; R2=PhCH2, R3=CO2H (claim 24). Guarna teaches the present 3-azabicyco[3.2.1]octan derivatives of general formula (I) in free form or in the form of pharmaceutically acceptable salts can be used for the preparation of pharmaceutical compositions following the usual pharmaceutical preparation methods [0052]; and Example 4 is (1S, 4R, 5R, 7S) -3,4-dibenzyl-2-oxo-6,8-dioxa-3-azabicyclo[3.2.1] octane-7-lysine carboxylate (compound of formula (I) where R1=R2=PhCH2, R3=COO- lysine+) [0064]. Example 4 of Guarna reads on the instantly elected species. Ischemia-reperfusion injury reads on an inflammatory disease characterized by uncontrolled immune response as evidenced by Guarna and Lutz et al (Journal of Inflammation, 2010; 7:27 pp 1-8, cited in the IDS filed October 14, 2022).
Guarna teaches ischemia-reperfusion is a pathological condition characterised by an initial restriction of blood flow to an organ followed by a subsequent restoration of perfusion and concomitant re-oxygenation; perhaps surprisingly, restoration of the blood flow and re-oxygenation is frequently associated with an increase in tissue damage and a profound inflammatory response (“reperfusion injury”). Moreover, Lutz teaches an important effect of hypoxia on a tissue is the development of metabolic acidosis; it occurs as a result of hypoxia when anaerobic glycolysis is the only way to generate energy; however, it can induce an inflammatory response when perfusion of the respective tissue is restored after hypoxia as well as hypothermia (page 2, left, last paragraph). Lutz teaches not only locally generated inflammatory mediators like cytokines/chemokines resulting from I/R injury but also systemic inflammatory mediators in the donor affect the graft after transplantation; here brain death profoundly contributes to a systemic inflammatory response through the release of cytokines from the brain; this "cytokine storm" deteriorates organ function resulting in more acute rejection episodes and decreased long-term function; the significance of such effects is underlined by experiments demonstrating the deleterious influence of brain death on graft function also over the long-term even when cold ischemia has been eliminated (page 2, right, 1st paragraph).
Regarding claim 7, Guarna teaches said pathologies or medical procedures include explant, preservation and reimplantation protocol for organs intended for transplantation including liver (claim 27). Liver transplantation ischemia reperfusion injury reads on an inflammatory disease characterized by production of pro-inflammatory cytokine that is downregulated by activation of ADAR1 as evidenced by Wang et al (Sci Rep, 2016; 6:20248 pp 1-10). Wang teaches ischemia/reperfusion (IR) is a major cause of liver damage during liver transplantation, hepatic resection, severe trauma, and hemorrhagic shock; excessive inflammation incurred by activation of the innate immune system plays a pivotal role in the initiation and progression of IR2, which shares some common pathways with infections caused by invading pathogens (page 1, 1st paragraph); ADAR1 plays an anti-inflammatory role by suppressing cytosolic innate immune signaling through its RNA-binding function under conditions simulating viral infection page 1, last paragraph); and histologic analysis revealed an obvious increase in liver injury with ADAR1 suppression and less damage when ADAR1 expression was enhanced (page 2, 6th paragraph).
Regarding claim 13, Guarna teaches these pharmaceutical compositions can comprise at least one of the present compounds of formula (I), or mixtures thereof, as active ingredient or adjuvant, possibly in combination with another active ingredient or adjuvant, selected according to the pathological conditions.
Thus, the teachings of Guarna anticipate the method of claims 1-7 and 13.
Response to Arguments
Applicant argues:
The teachings of Guarna are limited to reperfusion injury and that ischemia-reperfusion injury is not within the scope of inflammatory disease characterized by cytokine storm and/or uncontrolled immune response. It is clear that ischemia (i.e. hypoxia) triggers a cellular defense response so that a minority of the cells subjected to ischemia undergo necrosis while the majority of them undergo a metabolic imbalance which triggers apoptosis when then reperfusion occurs. It is therefore the reperfusion which produces the injury to the majority of cells which under oxidative stress, which no longer have the correct metabolism for properly manage re-oxygenation. The inflammation characterized by cytokine storm and/or uncontrolled immune response which is subject-matter of the present invention involves distinct and different biochemical pathways, and is typically caused by infective insults or is of autoimmune or genetic origin. I/R injury and inflammation characterized by cytokine storm and/or uncontrolled immune response, are actually distinct processes regulated by separate biochemical pathways. The present invention is directed to the treatment of inflammatory disease where I/R injury is completely absent.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As set forth above, Guarna teaches ischemia-reperfusion is a pathological condition characterised by an initial restriction of blood flow to an organ followed by a subsequent restoration of perfusion and concomitant re-oxygenation; perhaps surprisingly, restoration of the blood flow and re-oxygenation is frequently associated with an increase in tissue damage and a profound inflammatory response (“reperfusion injury”). Thus, Guarna establishes that ischemia-reperfusion injury is characterized by a profound inflammatory response which reads on an inflammatory disease characterized by uncontrolled immune response. This is further supported by Lutz, cited for evidentiary purposes, which teaches not only locally generated inflammatory mediators like cytokines/chemokines resulting from I/R injury but also systemic inflammatory mediators in the donor affect the graft after transplantation; here brain death profoundly contributes to a systemic inflammatory response through the release of cytokines from the brain; this "cytokine storm" deteriorates organ function resulting in more acute rejection episodes and decreased long-term function; the significance of such effects is underlined by experiments demonstrating the deleterious influence of brain death on graft function also over the long-term even when cold ischemia has been eliminated (page 2, right, 1st paragraph). Moreover, the instant specification a compound of the invention has a powerful anti-inflammatory and antiviral activity as it can determine a reduction in the systemic production of cytokines and consequent reduction of the effects deriving from the so-called "cytokine storm" in the patient, through the activation of ADAR1 and the consequent decrease of miR-101 and a reduction in the damage induced by the ischemia/reperfusion process that occurs in severe inflammatory states, through metabolic support to hypoxic tissues; hence, the compounds for use according to the present invention, as activators of ADAR1, are effective anti-inflammatory and antiviral agents, and are therefore useful for the treatment of diseases related to acute or chronic inflammation characterized by cytokine storm and/or uncontrolled immune response (see page 11, 2nd paragraph). Thus, ischemia/reperfusion injury reads on an inflammatory disease characterized by cytokine storm and/or uncontrolled immune response.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 8-11 of U.S. Patent No. 9,932,352. Although the claims at issue are not identical, they are not patentably distinct from each other because:
The present claims are directed to a method of treating inflammatory diseases characterized by cytokine storm and/or uncontrolled immune response, said method comprising administering to a subject in need thereof a compound of formula (I).
The previously allowed claims are directed to a method for treating an ischemia-reperfusion-related pathology or a surgical procedure involving ischemia-reperfusion injury, said method comprising administering to a patient in need thereof an effective amount of a compound of formula (I).
Ischemia-reperfusion injury reads on an inflammatory disease characterized by uncontrolled immune response as evidenced by Guarna and Lutz et al (Journal of Inflammation, 2010; 7:27 pp 1-8, cited in the IDS filed ).
Guarna teaches ischemia-reperfusion is a pathological condition characterised by an initial restriction of blood flow to an organ followed by a subsequent restoration of perfusion and concomitant re-oxygenation; perhaps surprisingly, restoration of the blood flow and re-oxygenation is frequently associated with an increase in tissue damage and a profound inflammatory response (“reperfusion injury”). Moreover, Lutz teaches an important effect of hypoxia on a tissue is the development of metabolic acidosis; it occurs as a result of hypoxia when anaerobic glycolysis is the only way to generate energy; however, it can induce an inflammatory response when perfusion of the respective tissue is restored after hypoxia as well as hypothermia (page 2, left, last paragraph). Lutz teaches not only locally generated inflammatory mediators like cytokines/chemokines resulting from I/R injury but also systemic inflammatory mediators in the donor affect the graft after transplantation; here brain death profoundly contributes to a systemic inflammatory response through the release of cytokines from the brain; this "cytokine storm" deteriorates organ function resulting in more acute rejection episodes and decreased long-term function; the significance of such effects is underlined by experiments demonstrating the deleterious influence of brain death on graft function also over the long-term even when cold ischemia has been eliminated (page 2, right, 1st paragraph).
Thus, the method of the previously allowed claims would anticipate the instantly claimed method.
Response to Arguments
Applicant argues:
Arguments directed to novelty rejections as provided above establish that the localized effects of ischemic injury cannot be considered equivalent to the inflammatory conditions cited in claims 1 and 6.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicant has not independently argued the merits of this rejection. Arguments regarding the distinctness of ischemic injury and the claimed inflammatory conditions have been addressed above. Therefore, the rejection is maintained for the reasons set forth on the record and for those set forth in the response to the arguments above.
Conclusion
Claims 1, 6, 7, 11, and 13 are rejected.
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RAYNA B RODRIGUEZ whose telephone number is (571)272-7088. The examiner can normally be reached 8am-5:00pm, Monday - Thursday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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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/Rayna Rodriguez/ Primary Examiner, Art Unit 1628
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