DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statements (IDS) comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Status of the application
Receipt of applicant’s remarks and claim amendments filed on 08/13/2025 are acknowledged.
In light of applicants claim amendments, previous 102 rejection is withdrawn.
However, applicants arguments for previous 112(a) written description and 103 rejections are found not persuasive, and accordingly the rejections are maintained and modified to address claim amendments. Please see the examiners response to applicants arguments below.
Response to Arguments
1. With regard to 112(a) written description rejection, applicants argue that while traversing the rejection, yet in the interest of expediting prosecution, claim 8 has been amended to include the limitation of non-rejected claim 10 and claim 13 has been amended to included the limitation of non-rejected claim 14, thereby rendering the rejection moot.
Previously claims 10 and 14 are not associated with independent claim 8. Both claims 10 and 10 belongs to independent claim 1. Though these incorporations changed the scope of claims 8 and 13, but these limitations do not overcome previous 112(a) written description rejection, as explained in the modified rejection.
2. With regard 103 rejection, applicants argue that the rejection is respectfully traversed. Since the allegedly primary reference of Nassoiy teaches away the claimed invention by stating that CXCR4 blockade promotes the development of ARDS rather than treating it, this prior art can't be combined to arrive at the claimed invention.
Nassoiy concludes that “In the present study, we tested how pharmacological modulation of CXCR4 influences the development of ARDS after unilateral lung ischemia-reperfusion injury. Our findings suggest that blockade of endogenous CXCR4 after lung ischemia- reperfusion injury promotes development of ARDS, whereas activation of CXCR4 delays development and attenuates severity of ARDS”.
There are no such limitations in the independent claim. Dependent claim 6 requires one of the recited conditions, such as recited injuries or viral infection. So, it can be a viral infection.
So, Nassroiy does not teach away treatment of human subjects with ARDS using a CXCR4 inhibitor as claimed.
Claim Rejections - 35 USC § 112 – Written Description [Maintained and modified]
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 8 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 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.
The independent claim 8 is drawn to a method of treating Coronavirus infection, the method comprising administering to a subject in need thereof a therapeutically effective amount of a CXCR4 inhibitor to thereby treat the Coronavirus infection, wherein said treating is not vaccination, and wherein said Coronavirus is SARS-Cov-2, Middle East respiratory syndrome Coronavirus or severe acute respiratory syndrome Coronavirus.
Dependent claim 13 is further comprises the use of a therapeutically effective amount of the recited anti-viral drugs.
Claims are broad with respect treating all possible coronavirus infections by administering all possible CXCR4 inhibitors. Claims are also broad with respect mode of administration, that means all possible administrations. Claims are broad with respect to subject population, that means all possible non-human mammalian animals.
Specification showed cytopathic endpoint assay for SARS and COVID-19 (Example 1) for SEQ ID NO:1 and it is not clear about end result or data, other than simple statement. In example 2, Clinical Protocol, to study the safety and efficacy of BL-8040 (a CXCR4 antagonist) set forth in SEQ ID NO:1 as treatment for patients with ARDS due to respiratory viral infections. But BL-8040 is a cyclic peptide, whereas SEQ ID NO:1 is a linear peptide. There is no clear definition or description about BL-8040.
Coronaviruses are a group of related RNA viruses that cause diseases in mammals and birds. In humans and birds, they cause respiratory tract infections that can range from mild to lethal. Mild illnesses in humans include some cases of the common cold (which is also caused by other viruses, predominantly rhinoviruses), while more lethal varieties can cause SARS, MERS and COVID-19. In cows and pigs they cause diarrhea, while in mice they cause hepatitis and encephalomyelitis [from Wikipedia].
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the broadly claimed subject matter, and if the variability results in unpredictability or uncertainties for the claimed subject matter, then specification must describe the possible uncertainties and provide possible solutions for the claimed method, so that a skilled person in the art can understands the invention and can reproduce the claimed invention. In its absence, it makes the invention unpredictable, and cannot be envisioned by a skilled person in the art. In this case, there are several diseases fall under coronaviruses by administering all possible CXCR4 inhibitors (existing and possible all future CXCR4 inhibitors), and there is no single known drug as of now to treat all possible diseases caused by all coronaviruses. Treatment methodology is also depends on the patient population and mode of administrations.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure (MPEP 2163(3)a(II)).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described.
The analysis for adequate written description considers the following:
(a) actual reduction to practice,
(b) disclosure of drawings or structural chemical formulas,
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure, and
(d) representative number of samples.
The issue is, will all possible CXCR4 inhibitors treat all possible diseases from all possible coronaviruses independent of type of population, with all possible mode of administrations? Do applicants provide enough description for all the variables in the broadly claimed subject matter and their association towards the end property, so that a skilled person in the art understands the claimed invention?
(a) actual reduction to practice and (b) disclosure of drawings or structural chemical formulas:
Specification described generically inhibitors of CXCR4 and SEQ ID NO:1 and its analogs. Exemplified data is limited to cytopathic endpoint assay for SARS and COVID-19 (Example 1) for SEQ ID NO:1 and it is not clear the end result. In example 2, Clinical Protocol, to study the safety and efficacy of BL-8040 (a CXCR4 antagonist) set forth in SEQ ID NO:1 as treatment for patients with ARDS due to respiratory viral infections. However, BL-8040 is a cyclic peptide of SEQ ID NO:1, and so claims require a linear peptide. Accordingly, shown data is not commensurate with the claimed subject matter.
No animal models are provided. Dosage amounts are very generic. No description or data is provided with any other CXCR4 inhibitors, any other coronaviruses and their associated diseases, subjects and modes of administrations etc.
No Drawings are provided
(c) sufficient relevant identifying characteristics in the way of complete/partial structure or physical and/or chemical properties or functional characteristics when coupled with known or disclosed correlation with structure:
Treating coronaviruses is probably one of the most unpredictable areas of biotechnology, as evidenced from COVID-19 pandemic. Treatment methodologies are expected to vary from virus to virus, drug to drug or subject to subject etc. Consequently, in light of dissimilarities in drug or disease(s) or population or mode of administration or combination, its outcome cannot be predicted in treating all possible disease of coronaviruses.
There are contraindications to known drugs to treat covid-19. For example, FDA list some drugs, those cannot be administered with Paxlovid [see page 4 in attached “Paxlovid patient eligibility screening checklist tool for prescribers”, 2024, FDA_Paxlovid_Doc].
There is also unpredictability in the mode of administration, for example, Bruno et al [Ther Deliv, 2013 Nov, 4(11), 1443-1467] teach the following:
While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed. [See abstract and whole article].
In view of above evidences, applicants have claimed wide range of diseases, subject population, and mode of administration etc., and a skilled person in the art can expect unpredictability for broadly claimed subject matter. However, there is no guidance as to which of the large genus of claimed subject matter in the disclosure. There are no physical/chemical/structural features that applicants have tied to this property in a relevant teaching manner, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed subject matter would be effective. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
(d) representative number of samples:
As explained above, specification showed cytopathic endpoint assay for SARS and COVID-19 (Example 1) for SEQ ID NO:1 and it is not clear about end result or data, other than simple statement. In example 2, Clinical Protocol, to study the safety and efficacy of BL-8040 (a CXCR4 antagonist) set forth in SEQ ID NO:1 as treatment for patients with ARDS due to respiratory viral infections. But BL-8040 is a cyclic peptide, whereas SEQ ID NO:1 is a linear peptide. There is no clear definition or description about BL-8040.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116).
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103 [Maintained and modified]
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1, 4-6, 11, 12, 15-18, 20-22, 26 and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Nassoiy (Clin Exp Pharmacol Physiol. 2018, 45, 16-26; see applicants filed IDS dated 04/07/2024) in view of Bonizzoli (Med Microbiol Immunol, 2016, 205, 371-379) and Bernhagen (WO2011038149A2; see applicants filed IDS dated 11/08/2022).
For claims 1 and 4:
Nassoiy discloses the effects of pharmacological CXCR4 modulation on the development of acute respiratory distress syndrome (ARDS) after lung injury. Nassoiy further discloses a method, wherein CXCR4 inhibitor, viz., AMD3100, attenuates progression of mild ARDS to moderate and severe ARDS. Finally, based on their shown data, Nassoiy concludes that CXCR4 as a new drug target to reduce the incidence and attenuate the severity of ARDS after lung injury. [see abstract, Fig. 1-6 and Discussion].
Difference is that Nassoiv silent on ARDS is associated with viral infection in a human subject. However, the following art cures this deficiency:
Bonizzoli teaches ARDS is associated with herpesviruses [see abstract].
Based on above, elevated levels of CXCR4 can be expected in the teachings of Bonizzoli, absent evidence to the contrary.
So, Nassoiy teaches CXCR4 attenuates progression of mild ARDS to moderate and severe ARDS, whereas ARDS can be a viral infection and can be associated with CXCR4 in the teachings of Bonizzoli, and so the combination reads claim.
For claim 6:
Bonizzoli teaches ARDS is associated with herpesviruses [see abstract].
Nassoiy discloses ARDS is associated with lung injury [see abstract].
For claim 11:
The disclosure of Nassoiy does not mention about administration of antigen of a pathogen causing said infection, and so, the methodology of Nassoiy reads this limitation.
For claim 12:
Nassoiy is silent on further use of anti-viral drug in their method.
Though it is a common practice to administer second drug to test additional effects, such as synergism etc., but this can be cured by teachings of Bernhagen, which teaches, in an analogous art, addition of second agent, such as interferon [see 00287-00289].
For claims 15-16:
Nassoiy is silent on a peptide as an inhibitor of CXCR4 or small molecule etc.
However, this can be cured from the teachings of Bernhagen, which teaches peptides as inhibitors of CXCR4 [see 0036-0038] in an analogous art.
In the disclosure of Nassoiy, the cited AMD3100 [see abstract] is a small molecule.
For claim 17:
Nassoiy is silent on applicants cited SEQ ID NO:1.
However, applicants already acknowledged that this peptide is already known as a CXCR4 inhibitor [see 12]. Applicants also acknowledged that the known CXCR4 inhibitors can be an organic compound, peptide, cyclic peptide, peptidomimetic compounds or antibodies etc [see pages 11-12]. Accordingly, these are equivalents for inhibition of CXCR4.
A case law holds that the mere substitution of an equivalent (something equal in value or meaning, as taught by Thornton) is not an act of invention; where equivalency is known to the prior art, the substitution of one equivalent for another is not patentable. See In re Ruff 118 USPQ 343 (CCPA 1958).
For claim 18 :
In the disclosure of Nassoiy, the cited AMD3100 [see abstract] is a small molecule.
For claim 20:
Nassoiy discloses the measurements of TNF-α, IL-6 and IL-10 levels [see in page 18, right column, third paragraph].
For claim 21:
Though mode of administration is ‘result effective’ limitation, but a skilled person in the art would determine suitable mode of administration through a routine experimentation, because of known well-established technology in the drug administration. Regardless, Nassoiy teaches injecting the drug for their disclosed method [see Fig.4]. Accordingly applicants specification, organic compounds and peptides as CXCR4 inhibitors and so these are equivalents, and so, the teachings of Nassoiy is expected to work for applicants claimed peptide.
For claims 22 and 26:
Nassoiy teaches sub micromolar concentrations per kg for CXCR4 inhibitor AMD3100, which is a small molecule, where as claimed peptide is a large and so, concentrations are expected to be higher.
Generally, concentrations of components for a given process is considered as result effective variables, and the differences in their amounts will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such differences in result-effective variables are critical. "Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results. As formulating optimal compositions for medicaments is routine in the art of pharmacology, the claims are considered to be prima facie obvious.
For claim 29:
Nassoiy is silent on the subject is infected with the cited limitation.
Bonizzoli teaches ARDS is associated with herpesviruses [see abstract].
For claim 30:
Nassoiy teaches reduced ratios of PaO2/FiO2 after AMD3100 administration, which is interpreted as favorable difference in PaO2/FiO2.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants CXCR4 inhibitors and utitlity in treating ARDS, various types of CXCR4 inhibitors and nexus between CXCR and viral diseases etc., were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). In the instant case, one is simply substituting a linker from Bonny into the composition of Abrahmsen.
Conclusion
THIS ACTION IS MADE FINAL. 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 SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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