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
This Office Action is in response to Applicant’s Arguments and Amendment filed, 07/24/2026, wherein the Amendment amended claims 1, 13-14, 16, and 23, cancelled claims 7-9, and 22, and added claims 24-26.
Claims 1, 3-6, 10-14, 16-21, and 23-26 are pending.
Priority
This application claims the following priority:
PNG
media_image1.png
101
637
media_image1.png
Greyscale
Election/Restrictions
Applicant elected a) inflammatory disease as the species of disease, and b) senicapoc, an inhibitor of the Gardos channel, as the species of compound, in the reply filed on 11/05/2025.
Claims 5-6, 11, and 20-21 are withdrawn from consideration as being directed to a non-elected subject matter.
Claims 1, 3-4, 10, 12-14, 16-19 and 23-26 are examined on the merits.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendments to the claims are sufficient to overcome these objections.
35 U.S.C. § 112(b)
Applicant’s amendments to the claims are sufficient to overcome these rejections.
35 U.S.C. § 102 and 103 over McNaughton-Smith, Bandeira, and Weiss
Applicant’s amendment to independent claim 1 that adds the limitation “wherein the subject is not suffering from sickle cell disease” is sufficient to overcome these rejections.
35 U.S.C. § 103 over McGraw, Bennett, and Weiss
On pg. 12, Remarks, Applicant persuasively argues that “Neither McGraw nor Bennett nor Weiss describe the presence of anemia of inflammation in patients with herpes simplex infection.”
REJECTIONS—MAINTAINED, MODIFIED, & NEW
Applicant’s amendment to claim 1 that deletes the term “prevention” and adds the limitation “wherein the subject is not suffering from sickle cell disease,” thereby modifying the patient population, has resulted in the below new rejections.
Claim Interpretation
-Claim 10 is interpreted as “wherein the treatment counteracts erythrocyte dehydration, counteracts loss of deformability of erythrocytes, and/or counteracts activation of one or more adhesion molecules expressed on erythrocytes.”
Claim Objections
(New) 14 and 23 are objected to because of the following informalities:
-In claim 14, the term “comprising” in line 1, should be replaced with - -wherein the method of treating the anaemia of inflammation comprises- -.
-In claim 23, the term “comprising” in line 1, should be replaced with - -wherein the method of treating the anaemia of inflammation comprises- -.
Appropriate correction is required.
Claim Rejections - 35 USC § 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.
(Slightly Modified) Claims 1, 3-4, 10, 12-14, 16-19 and 23-26 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 inhibiting the adhesion of red blood cells in patients with sepsis by administering a therapeutically effective amount of TRAM-34 or an anti-Darc antibody, does not reasonably provide enablement for a method for the treatment of anemia of inflammation comprising administering to a subject a therapeutically effect amount of a compound selected from the group consisting of a) an inhibitor of Ca2+ -activated potassium channel or b) an inhibitor of interaction of one or more chemokines with Duffy antigen receptor for chemokines. 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 criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
Independent claim 1 is directed toward a method for the treatment of any anemia of inflammation, caused by any condition or disease, comprising administering to a subject a therapeutically effect amount of a compound selected from the group consisting of a) any inhibitor of Ca2+ -activated potassium channel or b) any inhibitor of interaction of one or more chemokines with Duffy antigen receptor for chemokines.
As such, given the great breadth and variety of the patient population in combination with the great breadth of the compounds, the breadth of the claim is great.
Level of Skill in Art
The level of skill in the art is a clinician or a scientist with a PhD.
State of the Prior Art
Weiss (Anemia of Inflammation, Blood, published 2019, PTO-892 of 02/26/2026) teaches that anemia of inflammation (AI) is also referred to as anemia of chronic disease, and that it develops from systemic inflammation due to decreased production of erythrocytes accompanied by a modest reduction in erythrocyte survival (abstract).
On pgs. 43-45, Weiss teaches that it is challenging to diagnosis AI and that there is still a need for readily available and interpretable biomarkers that clearly differentiate between AI and iron deficiency anemia patients, to identify the best therapy and predict the therapeutic response.
Weiss teaches that when treating anemias, one has to consider whether such a treatment also impacts the underlying disease, which is of utmost concern when treating patients with infections or cancer (pg. 45).
Weiss teaches that the best treatment for AI is to cure the underlying inflammatory disease, i.e., treatments that target the infectious or inflammatory processes that causes anemia of inflammation will not only ameliorate the anemia but also improve many symptoms and deficits caused by the primary disease (pg. 46). “However, such fundamental treatments are not always possible or effective. With regard to treatments directed specifically at AI, we lack data from prospective trials about how aggressive such treatments should be or what constitutes the optimal therapeutic end point” (pg. 46).
Weiss teaches that two therapies have been established for the treatment of AI—iron supplementation and treatment with erythropoiesis-stimulating agents (ESAs), and that red blood cell transfusion is considered only as an emergency treatment in patients with severe anemia who are clinically unstable (pg. 46). However, concerns about the unrestricted use of ESAs in AI arose from studies showing higher mortality in patients with cancer or in dialysis (pg. 46).
Weiss teaches that prolyl hydroxylase inhibitors, which stabilize hypoxia-inducible factors, are being studied for the treatment of AI.
Weiss concludes by stating that “Our knowledge on the pathophysiology of AI has expanded dramatically over the past years, and we are gathering information on the therapeutic efficacy of established and novel emerging treatment strategies. However, we are still lacking information on optimal therapeutic start and end points for AI and are in need of identifying biomarkers that help to differentiate patients with AI from patients with iron deficiency” (pg. 47).
NIH (Anemia of Inflammation or Chronic Disease, PTO-892 of 02/26/2026) teaches that experts have not yet found a way to prevent anemia of inflammation (pg. 5). NIH further teaches that health care professionals typically treat anemia of inflammation by treating the underlying condition (pg. 5). NIH additionally teaches that the anemia can be treated with erythropoiesis-stimulating agents and blood transfusions, in severe cases (pg. 5).
In summary, the prior art teaches that anemia of inflammation is challenging to diagnose and that the best treatment is the treatment of the underlying disease causing the anemia of inflammation. The prior art additionally teaches that there are only a couple of treatments known for anemia of inflammation, iron supplementation and treatment with erythropoiesis-stimulating agents.
Predictability in the Art
Weiss teaches that:
-it is challenging to diagnosis AI and that there is still a need for readily available and interpretable biomarkers that clearly differentiate between AI and iron deficiency anemia patients, to identify the best therapy and predict the therapeutic response;
-when treating anemias, one has to consider whether such a treatment also impacts the underlying disease, which is of utmost concern when treating patients with infections or cancer;
-with regard to treatments directed specifically at AI, data is lacking from prospective trials about how aggressive such treatments should be or what constitutes the optimal therapeutic end point” (pg. 46);
-there are only two known therapies for AI; and
-“we are still lacking information on optimal therapeutic start and end points for AI.”
In view of the teachings of Weiss, the art of diagnosing and treating anemia of inflammation is unpredictable.
Working Examples
Example 1, beginning on pg. 22 studies the adhesion of donor RBC to laminin-alpha5 in response to IL-8 and sera from sepsis patients. For determining the effect of TRAM34, donor RBCs were first incubated with TRAM34 and then with IL-8 prior to the adhesion assay. For determining the effect of serum of sepsis patients, donor RBCs were first incubated with TRAM34 or anti-DARC antibodies and then with sera of sepsis patients (pg. 23).
Example 1 states that in AI, erythropoiesis is decreased and RBC destruction is exacerbated (pg. 24). The increased RBC destruction in AI is attributed to inflammation mediated hyperactivation of splenic macrophages. Incubation of RBCs with IL-8 induces a transient DARC-dependent rise of intracellular calcium levels in a subset of RBCs. This shows a direct effect of this pro-inflammatory chemokine on the integrity of RBCs, which may contribute to their degradation (pg. 25, Fig. 6). SDF-1, a chemokine, combined with IL-8 induces an even stronger calcium influx causing exacerbated loss of RBC deformability, leading to activation of adhesion molecules (pgs. 25-26). This data, indicates that healthy RBCs are targeted for destruction upon binding of IL-8 to DARN, contributing to the rapid decrease of circulating RBCs, which is what is observed in AI. Example 1 hypothesizes that the IL-8 dependent signaling response that is elicited in RBCs similarly occurs in erythroblasts, such that chronic inflammation may substantially impact erythropoiesis through DARC-mediated signaling (Fig. 7, pg. 26).
Pg. 26, lines 15-17 state, “In summary, we hypothesize that DARC-mediated signaling contributes to increased breakdown of RBC as well as to the inhibition of erythropoiesis in AI.”
Next the effect of an inhibitor of the Gardos channel in response to proinflammatory chemokines was assessed (pg. 26). The interaction between adhesion molecules and laminin-alpha5 and/or hyaluronic acid is assessed as a measure of RBC dehydration.
Erythrocyte adhesion to laminin-alpha5 and hyaluronic acid in response to IL-8 and sera of sepsis patients was assessed in the absence and presence of TRAM34, an inhibitor of the Gardos channel. Adhesion of donor RBCs in response to IL-8 incubation and sera of sepsis patients is inhibited by TRAM34 and anti-DARC antibodies (Fig. 8B, 8C pgs. 26-27).
Example 2, beginning on pg. 27, uses a mouse model in studying the efficacy of senicapoc on anemia of inflammation. However, this example is a prophetic example and the results are hypothesized.
Direction and Guidance
In view of the unpredictability of the art and the lack of working examples, the specification lacks sufficient direction and guidance to enable an ordinary skilled artisan to make and use the instant invention as claimed.
Quantity of Experimentation
In view of the lack of working examples, the unpredictability of the art, and the great breadth of the claims, the amount of experimentation required to determine which inhibitors of Ca2+ -activated potassium channel and which inhibitors of interaction of one or more chemokines with Duffy antigen receptor for chemokines, are effective in treating anemia of inflammation caused by which diseases, would be astronomical. This amount of experimentation would require starting at proof-of-concept, and proceeding through all levels of lead identification and optimization, This amounts to invention, not development; it is an undue amount of experimentation.
Thus, while being enabling for a method of inhibiting the adhesion of red blood cells in patients with sepsis by administering a therapeutically effective amount of TRAM-34 or an anti-Darc antibody, the instant specification does not reasonably provide enablement for a method for the treatment or prevention of anemia of inflammation comprising administering to a subject a therapeutically effect amount of a compound selected from the group consisting of a) an inhibitor of Ca2+ -activated potassium channel or b) an inhibitor of interaction of one or more chemokines with Duffy antigen receptor for chemokines.
Response to Arguments
On pg. 7, Remarks, Applicant argues that Example 1 shows that chemokines induce calcium influx in healthy erythrocytes, subsequently showing an increased expression of adhesion molecule. Applicant states that the calcium influx leads to a potassium efflux via Gardos channel accompanied by water efflux resulting in erythrocyte dehydration and inhibition of erythropoiesis. Applicant states that thus, healthy RBCs are targeted for destruction upon binding of chemokines to DARC, thus establishing DARC mediated signaling leads to RBC dehydration and subsequent destruction under inflammatory conditions, thus providing the scientific rationale underlying the claimed therapeutic models. Applicant states that “this Example investigates the response of healthy RBCs under inflammatory conditions, which is used as a model of anemia of inflammation.”
These arguments have been fully considered, but are not found persuasive. As discussed in the above rejection, instant Example 1 and the specification state:
Example 1 hypothesizes that the IL-8 dependent signaling response that is elicited in RBCs similarly occurs in erythroblasts, such that chronic inflammation may substantially impact erythropoiesis through DARC-mediated signaling (Fig. 7, pg. 26).
Pg. 26, lines 15-17 state, “In summary, we hypothesize that DARC-mediated signaling contributes to increased breakdown of RBC as well as to the inhibition of erythropoiesis in AI.”
It is respectfully pointed out that Applicant is relying on a hypothesized mechanism of action as “a model of anemia of inflammation.” Moreover, it is respectfully pointed out that the art does not teach such ex vivo mechanisms of action as “models of anemia of inflammation.”
While instant example 1 hypothesizes a mechanism of action and its effects in vivo, it provides no data substantiating how a hypothesized mechanism of action definitively correlates to a method of treat anemia of inflammation caused by any disease or condition by administering any inhibitor of Ca2+ -activated potassium channel or any inhibitor of interaction of one or more chemokines with Duffy antigen receptor for chemokines.
It is respectfully pointed out that Example 1 only definitely shows that TRAM34 and a specific anti-DARC antibody effectively decrease cell adhesion in the serum of sepsis patients.
And while Example 2 does provide a mouse model for studying anemia of inflammation, this example is a prophetic example and the results are hypothesized.
For these reasons, Applicant’s arguments are not persuasive to overcome the rejection.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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.
(New) Claims 1, 3-4, 10, 13-14, 16, 18-19 and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0042872 to Tubman (published 2018, PTO-892) in view of Clark (Human malarial disease: a consequence of inflammatory cytokine release, published 2006, PTO-892).
Tubman teaches a method of treating malaria by administering an inhibitor of the Gardos channel, wherein the inhibitor is senicapoc (pgs. 15, 16, 17 claims 1, 3-4, 20).
Tubman further teaches that “An important therapeutic pathway for treatment of malaria is preventing or retarding the dehydration of erythrocytes by manipulating the cellular ion fluxes of erythrocytes. Thus, in another aspect, the invention provides a method for reducing erythrocyte dehydration. The method comprises contacting an erythrocyte with an amount of a compound according to Formula (I) effective to reduce erythrocyte dehydration ([0066]).
While Tubman teaches a method of treating malaria, it differs from that of instant claim 1 in that it does not teach its methods as treating anemia of inflammation.
Clark teaches that malaria causes an acute systemic human disease that bears many similarities to those caused by bacteria, rickettsia, and viruses. Most of the pathology seen in all of these infectious diseases are explained by activation of the inflammatory system with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Clark teaches malaria as an inflammatory cytokine-driven disease that sequesters and drives anemia (abstract).
Clark teaches that critical illness associated with an inflammatory response invariably causes multifactorial anaemia. Thus, it can be a major component of malarial pathology. Clark teaches that poor red cell deformability is observed in malaria patients. Poor red cell deformability and dyserythropoiesis leads to severe anaemia in various disease, particularly in chronic infections such as malaria. Clark teaches dyserythropoiesis as a characteristic of malaria. “The effect on red cells of the combination of a lower rate of production and accelerated destruction can be expected to lead to severe anaemia” (pgs. 11-12, “Anaemia”; pg. 17, Figure 3).
As such, the patient population of patients with malaria, in view of the teachings of Clark, and the definition of “anaemia of inflammation” as taught on pg. 1 of the instant specification, includes patients with anaemia of inflammation. Moreover, Tubman teaches preventing or retarding the dehydration of erythrocytes by manipulating the cellular ion fluxes of erythrocytes, and the instant specification teaches erythrocyte dehydration as a hallmark of patients with anaemia of inflammation (see pg. 4 of the instant specification). Thus, an ordinary skilled artisan, would have reasonably expected the method of treating malaria taught by Tubman, that administers a therapeutically effective amount of senicapoc, would also treat anaemia of inflammation, as instantly claimed, since the method of Tubman administers the same active ingredient, in therapeutically effective amounts ([0069]-[0071] of Tubman), to the same patient population (patients with malaria, which causes anaemia of inflammation), since Tubman specifically teaches its methods as preventing or retarding the dehydration of erythrocytes.
Regarding claims 3-4, Tubman teaches senicapoc.
Regarding claims 10 and 24, MPEP 2111.04 states, a “‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’” Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In the instant case, the wherein clause expresses the desired result of the positive step of administering senicapoc, an inhibitor of Ca2+ -activated potassium Gardos channel, to a patient with anemia of inflammation. As such the method of Tubman meets the limitations of this claim.
Regarding claims 13 and 16, the combination of Tubman and Clark teach malaria as an inflammatory disease.
Regarding claims 14 and 23, while the combination of Tubman and Clark, does not explicitly teach “reducing or preventing erythrocyte dehydration in a subject suffering from chronic inflammation,” or “inhibiting potassium efflux from erythrocytes via the Ca2+ -activated potassium channel,” it is reasonable to assume that the method of the combination of Tubman and Clark, which teaches administering the same compound, senicapoc, an inhibitor of Ca2+ -activated potassium Gardos channel, in therapeutically effective amounts, to the same patient population (patients with malaria, a chronic inflammatory disease), as that taught by the instant specification and claims, would have the same properties as the instantly claimed invention. Moreover, the combination of Tubman and Clark teach its method as preventing or retarding the dehydration of erythrocytes by manipulating the cellular ion fluxes of erythrocytes, Thus, while the prior art does not explicitly teach these properties, burden is on Applicant to show that the prior art does not have these properties. See also MPEP 2112.02.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Regarding claims 18-19, senicapoc is an inhibitor of the Gardos channel.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over US 2018/0042872 to Tubman (published 2018, PTO-892) in view of Clark (Human malarial disease: a consequence of inflammatory cytokine release, published 2006, PTO-892), as applied to claims, 1, 3-4, 10, 13-14, 16, 18-19 and 23-24, and further in view of Ackerman (The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study, published 11/2020, PTO-892).
Tubman and Clark are applied as discussed above and incorporated herein.
The combination of Tubman and Clark differ from that of instant claim 12 in that it does not teach erythrocyte transfusion.
Ackerman teaches whole blood transfusion as associated with improved survival among children hospitalized with malaria and those with impaired consciousness or hyperlactatemia (pg. 2, “Interpretation”).
Ackerman teaches blood transfusion as a vital supportive measure in the treatment of severe malaria (pg. 3, bottom).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to add erythrocyte transfusion, i.e., whole blood transfusion, to the combined method of Tubman and Clark, to arrive at instant claim 12. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, to predictably arrive at a method that effectively treats children with severe malaria to optimize the treatment of the disease and quality of life for the malarial patient.
Free of the Prior Art
Claims 17 and 25-26 are free of the prior art.
Conclusion
No claims are 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 LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LAUREN WELLS/Examiner, Art Unit 1622
Prosecution Insights