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
Claims 1-17 are pending in the instant application.
Claims 1-17 are examined herein.
Priority
The instant application claims benefit of foreign priority to EP21198037.0, filed on 21 September 2021, and the benefit of priority to PCT/EP2022/076058, filed on 20 September 2022. The claims to the benefit of priority are acknowledged. As such, the effective filing date of the claims is 21 September 2021.
Information Disclosure Statement
The information disclosure statements (IDS), submitted on 21 March 2024 and 27 May 2026, are acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
Claim Interpretation
Claim 1 recites that X1 and X2 can be S. The instant specification presents no preferred embodiments where these substitution patterns are seen. However, the specification does present embodiments containing oxazoles. An Improper Markush rejection was considered but ultimately not set forth as thiazoles are known bioisosteric substitutions for oxazoles and one skilled in the art would consider the substitution obvious with a high expectation of retained activity.
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.
Claim 17 is 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 the treatment of iron metabolism disorders fails to provide the required enablement for the treatment of all diseases as a component of a combination therapy approach. 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 instant claim is drawn to a method for combination therapy comprising co-administration of a compound of claim 1 and an additional pharmaceutically active compound.The specification fails to provide information that would allow the one skilled in the art to practice combination therapy for any and all diseases and disorders.
To be enabling, the specification of the patent 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 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
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 the 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).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention - is a method for combination therapy comprising co-administration of a compound of claim 1 and an additional pharmaceutically active compound.
The state of the prior art - the pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate.
In order to prevent a disease: one would need to precisely identify those subjects likely to acquire such a disease, administer Applicant’s claimed invention, and demonstrate that the patient did not develop the disease as a result of the administration of the claim invention.
In the instant case, the prior arts recognize that therapeutic agents have potential to exhibit antagonistic property toward ferroportin, which can be used to treat iron metabolism disorders, such as thalassemia (Richard et al. Am J Hematol. 2019;95(1):68–77).
The predictability or unpredictability of the art – the law recognizes the pharmaceutical art as an unpredictable art and requires each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). Accordingly, the more unpredictable an area is the more specific disclosure is necessary in order to satisfy the statute. Section 2164.02 of the MPEP provides:
"[C]orrelation” as used herein refers to the relationship between in vitro and in
vivo animal model assays and a disclosed or a claimed method of use . . . if the
art is such that a particular model is recognized as correlating to a specific
condition, then it should be accepted as correlating unless the examiner has
evidence that the model does not correlate.
In light of these remarks, the Examiner finds that one of ordinary skill in the art would agree with the court; that is, the pharmaceutical art is unpredictable. Thus, a substantial correlation is necessary for establishing the potential of new therapeutics.
The amount of direction or guidance presented – the instant specification provides an explanation of the biological activity ferroporitin on pages 1-2, and discusses the implication of ferroportin inhibitors in the treatment of iron metabolism disorders. There is no direction or guidance provided that supports a use of ferroportin inhibitor as a drug in any combination therapy approach.
The amount of guidance or direction to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for treating any disease in combination with another therapeutic a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
The presence or absence of working examples - there are no working or prophetic examples in the specification that demonstrate that the instant compounds or compositions thereof may treat any disease in a combination therapy approach. The assays in the specification demonstrate that the instant compounds were tested for their ability to inhibit ferroportin.
The breadth of the claims – is incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the compounds of instant formula [insert] may prevent a [insert] disease in a patient.
The quantity of experimentation necessary – generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916. The article makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome.
For instance, Schafer et al. discloses: "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint.” It can be gleaned from this article that a plethora of experimentation is needed to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. See e.g., Horig et al. Journal of Translational Medicine 2004, 2(44) (“Successful drug development requires satisfying a matrix of domains from relevance to the disease and the drug-ability of the target through feasibility and convenience of drug delivery, demonstration of favorable benefit-risk profile in order to achieve a drug label that reflects physician and patent acceptance.") The Examiner finds that one of ordinary skill in the art would agree with the statements in these articles; that is, the amount of experimentation required to enable a pharmaceutical drug is extensive.
The level of skill in the art - the level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of those factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983).
Based on the typical education level of the active workers in the field of pharmaceuticals and/or medicine, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Therefore, claim 17 is rejected because the Examiner finds that the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, due to the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed illustrate that a person having ordinary skill in the art would not be able to treat any disease.
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 1-8 , 10, and 12-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 41, 49-50, and 52-58 of co-pending Application No. 18/556,128 (reference application) in view of Patani et al. (Chemical Reviews. 1996;96(8):3147-3176). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 1-4 and 7-8 the reference application recites compounds of Formula (I) (claim 41) (pictured below) which belong to the instant genus when:
I is 1 to 2
m is 1, 2, or 3
n is 1, 2, or 3
X1 is N, S, or O
X2 is N, S, O, or CR4; wherein R4 is H, halogen, C1-3- alkyl, or C1-3- haloalkyl
A is (a-1) (pictured below)
B is (b-1), (b-2), or (b-3) (pictured below)
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The reference application does not teach the instant R4 to be methyl, rather H is taught.
Patani teaches that hydrogen and methyl are bioisosteres (Table 12; page 3153).
It would be prima facie obvious to one of ordinary skill in the art to modify the reference teaching of 1H-1,3-benzodiazole and 3a,4,5,6,7,7a-hexahydro-1H-1,3-benzodiazole for B to 1-methyl-1H-1,3-benzodiazole and 1-methyl-3a,4,5,6,7,7a-hexahydro-1H-1,3-benzodiazole, respectively, under the teaching of Patani.
Regarding claim 5, the reference application recites X1, X2, and X3 are selected to form the following groups (claim 49):
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Regarding claim 6, the reference application recites group A to be (claim 50):
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Regarding claim 10, the reference application recites a medicament comprising a compound of Formula (I) (clam 52).
Regarding claim 12, the reference application recites a method of prophylaxis or treatment of an iron metabolism disorder (claim 53).
Regarding claim 13, the reference application recites the iron metabolism disorder to be thalassemia, alpha-thalassemia, beta-thalassemia, deltathalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, hemolytic anemia, sickle cell anemia, and congenital dyserythropoietic anemia (claim 54).
Regarding claim 14, the reference application recites the method wherein the iron metabolism disorder is one or more selected from: diseases associated with ineffective erythropoiesis, myelodysplastic syndromes, MDS, myelodysplasia, congenital dyserythropoietic anemia, myeloproliferative neoplasms, polycythemia vera; diseases caused by reduced levels of hepcidin; infections caused by pathogenic microorganisms or the bacterium Vibrio vulnificus; neurodegenerative diseases, Alzheimer's disease, or Parkinson's disease; formation of radicals, reactive oxygen species (ROS) and oxidative stress; cardiac, liver and/or endocrine damage caused by iron overload; and inflammation triggered by excess iron (claim 55).
Regarding claim 15, the reference application recites a medicament comprising a compound of Formula (I) and an additional therapeutic (claim 56).
Regarding claim 16, the reference application recites the medicament in the form of a formulation for oral or parenteral administration (claim 57).
Regarding claim 17, the reference application recites a method for combination therapy comprising administration of a compound of Formula(I) and an additional therapeutic (claim 58).
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 (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 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) 1-8 and 10-17 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dürrenberger et al. (WO2017068089A2) in view of Patani et al. (cited above).
Regarding claims 1-4 and 6-8, Dürrenberger discloses compounds of formula(I) (claim 1) and formula (Vc-1) (claim 28) (pictured below). These compounds are species of the instant genus when the reference
R1 is optionally substituted alkyl
R2 is H
R3 is H
Z is a 5 membered heteroaryl
A1 is an optionally substituted alkanediyl
A2 is an optionally substituted alkanediyl; or forms a 4-7 membered ring with R3
Ar is an optionally substituted bicyclic heteroaryl
R5 is halogen
Y2 is C
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Dürrenberger discloses preferred embodiments 94, 127, 193, and 208 (pictured below), which are species of the instant genus apart from the 1H-1,3-benzodiazole.
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Dürrenberger does not teach substitution of the hydrogen correlating to the instant R4 of the benzodiazole.
Patani teaches that hydrogen and methyl are bioisosteres.
It would be prima facie obvious to one of ordinary skill in the art to substitute the 1H-1,3-benzodiazole of the reference compounds with 1-methyl-1H-1,3-benzodiazole to arrive at the instant invention. As Patani teaches the methyl and hydrogen to be isosteres, the skilled artisan would have a reasonable expectation of success and retained activity.
Regarding claim 5, Dürrenberger teaches formula (IIa), which limits Z (pictured below) (claim 8) to a 5 membered heteraryl where X1 is C, N, S, or O; X2 is C or N; X3 is C, N, S, or O; and X4 is C, N, S, or O.
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Regarding claim 9, Dürrenberger teaches preferred embodiment 127 (pictured below). N-substitution of hydrogen for methyl on the benzodiazole, as guided by Patani, results in the instant compound 5 (pictured below).
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Regarding claim 10, Dürrenberger teaches a medicament comprising a compound of formula(I) (claim 44).
Regarding claim 11, Dürrenberger teaches a method of using the compounds of formula(I) in the inhibition of iron transport mediated by ferroportin (claim 33).
Regarding claim 12, Dürrenberger teaches the method of treating a disease caused or related to increased iron levels, increased iron absorption or iron overload (claim 33).
Regarding claim 13, Dürrenberger teaches the method of treating a disease wherein the diseases related to or caused by increased iron levels, increased iron absorption or iron overload are selected from thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, hemolytic anemia (claim 37).
Regarding claim 14, Dürrenberger teaches ferroportin inhibitors for the use in the prophylaxis and/or treatment of diseases associated with ineffective erythropoiesis (claim 34); a disease caused by reduced levels of hepcidin (claim 35); an infection caused by pathogenic microorganisms (claim 36); a neurodegenerative disease (claim 40); formation of radicals, ROS, or oxidative stress (claim 41);cardiac, liver and endocrine damage (claim 41), and/or inflammation triggered by excess iron (claim 43).
Regarding claim 15, Dürrenberger teaches a medicament comprising a compound of formula (I) (claim 44), one or more pharmaceutical carriers and/or auxiliaries and/or solvents (claim 45) , and one additional pharmaceutically active compound.
Regarding claim 16, Dürrenberger teaches the medicament in the form of a formulation for oral or parenteral administration (claim 50).
Regarding claim 17, Dürrenberger teaches the method of combination therapy comprising a compound of formula (I) and an additional therapeutic (claim 51).
Conclusion
Claims 1-17 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
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, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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