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 .
DETAIL ACTION
This office action is a response to Applicant’s amendment/reply filed 11/26/2025
As filed, claims 1-13 are pending, wherein claims 1, 2, and 10 are independent claims.
Election/Restrictions
Regarding the election of species requirement, Applicant elected the species of reparixin for the instantly claimed inhibitor of the CXCL8 receptor, which can be found in paragraph 0074 of the instant specification. The claims, which read on the elected species, are instant claims 1-13, according to Applicant’s reply filed 11/26/2025.
Examination will begin with the elected species. In accordance with the MPEP 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non-elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species . Should Applicant overcome the rejection by amending the claim, the amended claim will be reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As per MPEP 803.02, the Examiner will attempt to determine whether the entire scope of the claims is patentable. Applicants' elected species, as shown above, does makes a contribution over the prior art. Therefore, according to MPEP 803.02: should the elected species appear allowable, the search of the Markush-type claim will be extended. The search and examination should be continued until either (1) prior art is found that anticipates or renders obvious a species that falls within the scope of a proper Markush grouping that includes the elected species, or (2) it is determined that no prior art rejection of any species that falls within the scope of a proper Markush grouping that includes the elected species can be made. The Examiner need not extend the search beyond a proper Markush grouping.
Because the Markush-type claims (i.e. claims 1, 2, and 10) are determined to be free of prior art, the election of species requirement is hereby withdrawn.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 1/29/2024 have been considered by the Examiner.
Drawings
The drawings of Figs 3A-3D, 3F, 4C-4E, 5A-5C, 5F, 5G, 6E, 7K, 8A, 8C-8J, 10B, 10D, 11A, and 11C-11F are objected to because the texts and/or numbering are blurry and illegible. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 1-3 and 6-13 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 2, and 10 recite the limitation, “inhibitor of the CXCL8 receptor”, in reference to the instantly claimed processes. Applicant has not described the claimed genus of “inhibitor of the CXCL8 receptor” in a manner that would indicate they were in possession of the full scope of this genus, or even to describe what this genus is comprised of.
Regarding the requirement for adequate written description of chemical entities, Applicant's attention is directed to the MPEP §2163. In particular, Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plain for obtaining the claimed chemical invention." Eli Lilly, 119 F.3d at 1566. The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office ("PTO") Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.1 "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5, 2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter aria, "functional characteristics when coupled with a known or disclosed correlation between function and structure..." Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106 (emphasis added)). Moreover, although Eli Lilly and Enzo were decided within the factual context of DNA sequences, this does not preclude extending the reasoning of those cases to chemical structures in general. Univ. of Rochester v. G.D. Searle & Co., 249 Supp. 2d 216, 225 (W.D.N.Y. 2003).
In the instant case, the claimed “inhibitor of the CXCL8 receptor” encompasses any known and unknown molecule (e.g. compound, siRNA, antibody, etc.) that can inhibit CXCL8 receptor. Applicants described a number of small molecule CXCL8 inhibitors, anti-CXCL8 antibodies, etc. as examples of “an inhibitor of the CXCL8 receptor” (paragraphs 0035-0074), which are not described adequately enough to allow one skilled in the art to ascertain that Applicant is in possession of the entire scope of that genus. Applicants have not described this genus in a manner that would allow one skilled in the art to immediately envisage the compounds contemplated for use.
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 the claimed “inhibitor of the CXCL8 receptor”. The prior arts disclosed that the CXCL8 receptor inhibition can be achieved through competitive or non-competitive mechanism. See Adage et al., PA401, a novel CXCL8-based biological therapeutic with increased glycosaminoglycan binding, reduces bronchoalveolar lavage neutrophils and systemic inflammatory markers in a murine model of LPS-induced lung inflammation. Cytokine, 2015, 76, 433-441; and Casilli et al., Inhibition of interleukin-8 (CXCL8/IL-8) responses by repertaxin, a new inhibitor of the chemokine receptors CXCR1 and CXCR2. Biochemical Pharmacology, 2005, 69, 385-394.
As such, the claims lack adequate written description for the claimed “inhibitor of the CXCL8 receptor”.
Regarding claims 3, 6-9, and 13, these claims are directly or indirectly dependent of claim 1, and they failed to correct the defective issue in claim 1, which rendered these claims improper.
Regarding claims 11 and 12, these claims are dependent of claim 10 and they failed to correct the defective issue in claim 10, which rendered these claims improper.
Claims 1 and 3-13 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 therapeutically treating CMML, does not reasonably provide enablement for prophylactically treating (i.e. preventing) CMML. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
As stated in the MPEP § 2164.01(a): “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is ‘undue’.” In In re Wands (8 USPQ2d 1400 (Fed. Cir. 1988)), the Federal Circuit established that the following factors are to be considered when determining whether a disclosure meets the enablement requirement of the first paragraph of 35 U.S.C. § 112:
The nature of the invention - is a method of treating CMNML via an inhibitor of the CXCL8 receptor. However, the word, “treating”, embraces prophylactic language, according to paragraph 00112 of the instant specification.
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 failed to recognize that CXCL8 inhibitor has been used to therapeutically or prophylactically treating CMML.
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 briefly provides an explanation of the pathogenesis of CMML on pp. 1-2 of the instant specification. There is no direction or guidance provided that supports a use of the inhibitor of the CXCL8 receptor as a drug for prophylactically treating (i.e. preventing) CMML, as instantly embraced.
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 prophylactically treating (i.e. preventing) CMML, 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 inhibitors of the CXCL8 receptor or composition thereof may prophylactically treating (i.e. preventing) CMML, as instantly embraced. The assays in the specification demonstrate that the reparixin or ladarixin (i.e. CXCL8 receptor inhibitor) restored the proliferation of wildtype CD34+ cells (paragraph 00171 of the instant specification).
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 inhibitors of the CXCL8 receptor may prophylactically treating (i.e. preventing) CMML 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.
Conclusion – Claims 1 and 3-13 are 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 prophylactically treating (i.e. preventing) CMML.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-13 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.
Regarding claims 1, 2, and 10, the claims recite the phrase, “the CXCL8 receptor”, wherein the word, “the”, requires antecedent basis, and it is unclear where applicant has defined “a” CXCL8 receptor. Without antecedent basis, the claims are rendered indefinite.
Regarding claim 9, the claim recites the phrase, “the suppressive potential of IGRANs”, wherein the word, “the”, requires antecedent basis, and it is unclear where applicant has defined “a” suppressive potential of IGRANs. Without antecedent basis, the claim is rendered indefinite.
Regarding claims 3-9 and 13, these claims are directly or indirectly dependent of claim 1, and they failed to correct the indefiniteness issue of claim 1, which rendered these claims indefinite.
Regarding claims 11 and 12, these claims are dependent of claim 10, and they failed to correct the indefiniteness issue of claim 10, which rendered these claims indefinite.
Claim Objections
Claims 2, 4-6, 9, and 10 are objected to because of the following informalities:
Regarding claim 2, the claim recites the phrase, “for maintaining or enhancing the proliferation of wildtype hematopoietic stem cells”.
Such expression can be clarified by reciting -- for maintaining or enhancing
Regarding claim 4, the compound “meraxin” is a synonym of the compound “ladarixin”. Since the two names are drawn to the same compound, one of these names should be removed.
Regarding claim 5, the claim recites the phrase, “wherein said CXCL8 receptor inhibitor is reparixin compound of formula”.
Such expression can be clarified by reciting -- wherein said CXCL8 receptor inhibitor is reparixin having the formula of --.
Regarding claim 6, the claim recites the phrase, “by wildtype hematopoietic stem cells so as to enhance their proliferation”.
Such expression can be clarified by reciting -- by wildtype hematopoietic stem cells so as to enhance of the wildtype hematopoietic stem cells --.
Regarding claim 9, the claim recites the phrase, “suppressive potential of IGRANs”.
Such expression can be clarified by reciting -- suppressive potential of immature granulocytes (IGRANs) --.
Regarding claim 10, the claim recites the phrase, “measuring the amount of immature granulocytes (IGRANs) in a sample of blood of said subject, and/or measuring the level of circulating CXCL8”.
Such expression can be clarified by reciting -- measuring
Regarding claim 10, the claim recites the phrase, “high level of circulating CXCL8 in their blood”.
Such expression can be clarified by reciting -- high level of circulating CXCL8 in of the subject --.
Appropriate correction is required.
Conclusion
Claims 1-13 are rejected.
Claims 2, 4-6, 9, and 10 are objected.
The instant claims are drawn to a method of treating CMML via an inhibitor of CXCL8 receptor; and using an inhibitor of CXCL8 receptor to treat CMML do not appear to have been disclosed previously in the prior arts. For at least this reason, the instant claims are substantially differentiated from any prior art reference, such as U.S. Patent Application Publication No. 2018/0177808, hereinafter Zebala. Furthermore, the prior art provide insufficient guidance or motivation that would have led a person having ordinary skill in the art to arrive at the instantly claimed process.
Telephone Inquiry
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PO-CHIH CHEN whose telephone number is (571)270-7243. The examiner can normally be reached Monday - Friday 10:00 am to 6:00 pm.
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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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/PO-CHIH CHEN/Primary Examiner, Art Unit 1621