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 .
Priority
Acknowledgments are made that this application claims the priority to the following:
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Information Disclosure Statement
Filed 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.
Response to Election of Species
Applicant's response to election of species in the reply filed on 11/10/2025 and supplemental claim amendments filed on 04/28/2026 is acknowledged.
Examiner also acknowledges applicants cancelation of claims 104-129 and newly added claims 130-155.
All species are examined on merits in this office action, and so, previous election of species is withdrawn.
Claim objections
(i) Claim 135 is objected to because of the following informalities: claim further limits and recites method of treating viral infection, which is totally different and divergent method from that of its independent claim 130. Appropriate correction is required.
(ii) Claim 150 is objected to because of the following informalities: claim recites “(PO)/IV” in the claim language. If it is oral administration followed by IV, then it should be clearly stated as separate limitations. Appropriate correction is required.
(ii) Claim 153 is objected to because of the following informalities: claim recites “1.5 mg/day once a day”. “once a day” should be removed because it is redundant. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 132, 137-147, 150 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 pre-AIA the applicant regards as the invention.
(i) The claims 132, 137-139, 150 recite limitations in the parenthesis, other than abbreviations, which renders the claims indefinite because it is unclear whether the limitations following parenthesis are part of the claimed invention. MPEP 2173(d) does not say anything about parenthesis, however, MPEP 2173.05(d) states that Exemplary Claim Language ("for example," "such as") [R-07.2015] Description of examples or preferences is properly set forth in the specification rather than the claims. In this case, it can mean “for example” or “such as”. Accordingly claims 132, 137-139, 150 and their dependents are rendered indefinite.
(ii) Claims 132, 137-139, 146-147 and 150 recite word “including” several times. What is excluded ??? This is not the proper way to write the claims. The meaning of “including” can be “embrace imply containing parts of a whole”. Having said that it is not clear whether applicants limiting the conditions to the recited ones, or to other known conditions. Accordingly, claims 132, 137-139, 146-147, 150 and their dependents are rendered indefinite.
(iii) Claims 146-147 and 150 recite a broad range or limitation together with a narrow range.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Accordingly, claims 146-147, 150 and their dependents are rendered indefinite.
(iv) Claim 155 recited dexamethasone, whereas independent claim does not have this limitation. There is insufficient antecedent basis for this limitation in the claim.
Claim Rejections - 35 USC § 112 – Written Description
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 130-155 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 for the claimed method. 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 rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:
Independent claim 130 is drawn to a method of treating inflammation to a patient in need thereof, comprising administering to said patient a therapeutically effective amount of plitidepsin (PLD) or a pharmaceutically acceptable salt thereof; wherein PLD or a pharmaceutically acceptable salt thereof is administered as an IV infusion.
Dependent claim 131 limits inflammation to inflammation associated with toll-like receptors.
Remaining dependent claims directly depend on independent claim 130 or indirectly through the dependent claim 131.
Inflammation is a process, which can take place individually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammation reaction. There is no common mechanism by which all, or even most, inflammation arise. Mediators include bradykinin, serotonin, C3a, C5a, histamine, assorted leukotrienes and cytokines, and many, many others. Accordingly, treatment of inflammation is exceedingly complex, and there is known single drug available to treat all possible inflammations (originated from different pathways). There are several types of toll-like receptors and these act differently to activate pro-inflammatory mediators.
Claims are also broad with respect to patient population, that means all possible human and non-human patients. Claimed effective amount can be any range.
To support the above claimed divergent subject matter, the description and working examples provided in the specification are very limited. In shown examples, applicants described or shown inhibition of NFkB and cytokines, viz., IL-1, IL-6, IL-8 and TNF-alpha. Further applicants observed that PDL was able to significantly reduce the secretion of IL-6, IL-10, TNF-alpha induced by LPS-B5 and decrease the percentage of macrophages presents on bronchoalveolar lavage without cytotoxic effects.
So, the issue is in the scope of the broadly claimed subject matter in treating inflammation by administering effective amount of PDL. Specification failed to describe the nexus between the shown data and divergent claimed subject matter. In other words, the structure/function relationship for the claimed generic variables and claimed method is not described.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a divergency in the genus or broadly claimed subject matter, and if it expects unpredictability for the claimed method, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed method. In this case, inflammation is heterogeneous and probably one of the most unpredictable areas in medicine and consequently, the effects of treating the inflammation cannot be predicted. So, the absence of description with divergent species makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
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. See MPEP 2163 II(A)(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 question is with large divergency in inflammation, did applicants provide enough description for treating all possible inflammations by administering PDL? or will a skilled person in the art understand the claimed invention based on the guidance and provided description in the specification?
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Not provided. Though the mediators for inflammation include bradykinin, serotonin, C3a, C5a, histamine, assorted leukotrienes and cytokines etc., but the described data is limited to inhibition of NFkB and its association with cytokines, viz., IL-1, IL-6, IL-8 and TNF-alpha. Further applicants described that PDL was able to significantly reduce the secretion of IL-6, IL-10, TNF-alpha induced by LPS-B5 and decrease the percentage of macrophages presents on bronchoalveolar lavage without cytotoxic effects. Patient population is also not described. Described dosage amounts are very generic. So, the provided data is very limited.
Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
Fig. 1-2 describes that NFkB transactivation in response to the activation of Toll-like receptors is inhibited by PLD, which leads to increase in secretion of pro-inflammatory cytokines.
Fig.3 describes the ex-vivo down-regulation of cytokines IL-6, IL-10 and TNF-alpha by PLD.
Fig. 4 describes decrease in classically activated macrophages in LPS-challenged mice.
Fig. 5 descibes the effects of PLD on alveolar macrophage recruitment in LPS treated mice.
It appears that the remaining figures are related to anti-viral activities by PLD.
So, as evidenced from the above description of drawings, it is clear that the claimed invention is not complete, since limited to inhibition of NFkB and its association with cytokines, viz., IL-1, IL-6, IL-8 and TNF-alpha, by a reduction to drawings that are not sufficiently detailed to show that applicant was in possession of the claimed invention as a whole.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
There is no common mechanism by which all, or even most, inflammation arise. It appears that applicants described data fails to establish a fact that shown data treats all types of inflammation in a patient in need thereof. Based on the established art, the fact is that molecular mechanism underlying inflammation is very divergent and not completely known, see below some evidences from the known art:
Gusev [Int.J.Mol.Sci., 2022, 23(9), 4596, 1-41] describes that inflammation is a universal response of an organism to predominantly local tissue alterations of diverse nature. According to the canons of general pathology, inflammation is a typical complex (local and systemic) general pathological process which forms the basis of disease pathogenesis with a variety of inflammatory focus localizations and symptomatology. Classical (canonical) inflammation is characterized by a stereotypic complex of vascular changes, which lead to edema followed by migration of leukocytes to the damaged area and formation of an inflammatory focus. The presence of a focus of inflammation is a key attribute of different variants of classical inflammation and its distinguishing feature from non-classical variants of inflammation. [see Introduction].
Ahmed [Front.Biol., 2011, 6(4), 274-281] describes the fact that to date, a number of pattern recognized receptors have been identified with the selective ability to detect pathogen associated molecular patters, danger associated molecular patterns or both and these include Toll-like receptors (TLRs), C-type lectin receptors (CLRs), RIG-1-like receptors (RLRs) and NOD-like receptors (NLRs). [see page 275, right column, 1st paragraph].
Medzhitov [Nature, 24 July 2008, vol.454, 428-435] describes that at a basic level, the acute inflammatory response triggered by infection or tissue injury involves the coordinated delivery of blood components (plasma and leukocytes) to the site of infection or injury. This response has been characterized best for microbial infections, in which it is triggered by receptors of the innate immune system, such as Toll-like receptors (TLRs) and NOD (nucleotide-binding oligomerization-domain protein)-like receptors (NLRs). This initial recognition of infection is mediated by tissue resident macrophages and mast cells, leading to the production of a variety of inflammatory mediators, including chemokines, cytokines, vasoactive amines, eicosanoids and products of proteolytic cascades [see right column in page 428]. Further describes that the pathological potential of inflammation is unprecedented for a physiological process. Although the destructive ability of infection-induced inflammation is understandably unavoidable, the pathogenic capacity of other types of inflammation is puzzling. A major unresolved problem is defining the normal physio logical counterpart of the systemic chronic inflammatory state [see Conclusions].
In view of above evidences, applicants have claimed treating all possible inflammations, and a skilled person in the art can expect unpredictability in the broadly claimed genus. 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 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.
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.
Conclusion
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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