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 1-15 and 17-18 are pending in the present application file.
Priority
The following continuity data is acknowledged in the present application file:
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Information Disclosure Statement
The Information Disclosure Statement(s) filed December 2, 2024 has been acknowledged by the Examiner. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the Examiner.
Claim Interpretation
Regarding the limitation of “able to bind to human DPP9”, recited in present claim 1, these limitations are interpreted as an intended use for the compounds of present Formula I and thus not given patentable weight. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.
Regarding an intended use limitation, MPEP 2111.02(II) notes:
“If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction. See Shoes by Firebug LLC v. Stride Rite Children’s Grp., LLC, 962 F.3d 1362, 2020 USPQ2d 10701 (Fed. Cir. 2020)”.
In this situation, the limitation does not affect the structure of a compound of Formula I. If the prior art structure is capable of performing the intended use, then it meets the claim. The present claims are interpreted for the purposes of applying prior art as a compound comprising the present Formula I of the present claims.
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 DPP9 enzyme-related disorders, does not reasonably provide enablement for both the treatment and prevention of any and all disorders. 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.
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 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
the nature of the invention,
the state of the prior art,
the predictability or lack thereof in the art,
the amount of direction or guidance present,
the presence or absence of working examples,
the breadth of the claims,
the quantity of experimentation needed, and
the level of the skill in the art.
In the instant case,
The nature of the invention
The nature of the invention of claim 17 is the method for the prevention and/or treatment of a disorder comprising administering to a subject in need thereof a compound of formula I of claim 1. Applicant provides where in an aspect or embodiment, the disorder is a “DPP9 enzyme-related disorders comprising cancer where the tumor cells are expressing DPP9” (see page 3, lines 22-25 of instant specification). The instant specification teaches where the disease is a DPP9 enzyme-related disorder (see page 26, lines 4-6).
The state of the prior art and The predictability or lack thereof in the art
The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. what compounds can treat which specific disease by what mechanism). There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
While it is rare for a protease to cleave a peptide bond after a proline residue, proteases of the dipeptidyl peptidase IV (DPP-IV/DPP4) family, which includes DPP9, DPP8 and fibroblast activation protein (FAP), have such an ability and exert significant functions in the pathogenesis of diabetes, tumor biology and immunoregulation (Zhang, Hui, et al. "Dipeptidyl peptidase 9 subcellular localization and a role in cell adhesion involving focal adhesion kinase and paxillin." Biochimica Et Biophysica Acta (BBA)-Molecular Cell Research 1853.2 (2015): 470-480.). See page 470 of Zhang et al.
Further From Zhang et al. on page 470:
DPP9 is ubiquitously expressed in normal tissues from mouse, human, baboon, cynomolgus monkey and Sprague Dawley rat. The expression of DPP9 is altered in many disease conditions, such as in liver disease, inflamed lungs, inflammatory bowel disease and chronic lymphocytic leukemia.
Emerging evidence points to the role of DPP9 in a number of cellular processes, including extracellular matrix (ECM) interactions, proliferation and apoptosis.
DPP9 knockdown and activity inhibition reduce cell adhesion and migration, indicating that DPP9 might be a potential therapeutic target for limiting tumor growth and metastasis. See page 479 of Zhang et al. The recent discovery of potential DPP9 substrates that have roles in cancer cell metabolism also points towards the potential of DPP9 inhibition as a cancer therapy.
DPP8/9 inhibitors induce pyroptosis in the majority of human acute myeloid leukemia (AML) cell lines and primary AML samples, but not in cells from many other lineages, and that these inhibitors inhibit human AML progression in mouse models. Overall, this work identifies an activator of CARD8 in human cells and indicates that its activation by small-molecule DPP8/9 inhibitors represents a new potential therapeutic strategy for AML. (Johnson, Darren C., et al. "DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia." Nature medicine 24.8 (2018): 1151-1156.). ”[I]nhibition of two intracellular serine dipeptidases Dpp8 and Dpp9 (Dpp8/9) by Val-boroPro activates the inflammasome sensor protein Nlrp1b in murine macrophages, which in turn activates pro-caspase-1 and triggers a lytic form of cell death known as pyroptosis”. See Johnson et al. page 1151, left column.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute.
The present claimed invention is highly unpredictable as discussed below:
From Wagner, Leona, et al. "Unravelling the immunological roles of dipeptidyl peptidase 4 (DPP4) activity and/or structure homologue (DASH) proteins." Clinical & Experimental Immunology 184.3 (2016): 265-283.:
Detailed understanding of the pathophysiological role of the enzymes and the functional differentiation between DPP8 and DPP9, is nonetheless not within close reach. Contributing to this knowledge void and to the scarcity of reliable translational research results, is the absence of inhibitors that are able to discriminate between DPP 8 and 9. Indeed, both enzymes share a remarkably high sequence homology, amounting to an overall 77% amino acid similarity (aas). The aas further increases to 100% within the enzymes' active sites, rendering discovery of selective DPP8 or DPP9 inhibitors a very challenging task. In addition, both enzymes have intracellular localization and are present simultaneously in most cell types that so far have been investigated. The latter further complicates the interpretation of functional characterization experiments.
From Zhang et al. page 479, right column:
DPP9 knockdown and activity inhibition reduce cell adhesion and migration, indicating that DPP9 might be a potential therapeutic target for limiting tumor growth and metastasis. The recent discovery of potential DPP9 substrates that have roles in cancer cell metabolism also points towards the potential of DPP9 inhibition as a cancer therapy. However, selective inhibitors targeting DPP9 only and conditional DPP9 knock-out mice would greatly facilitate future investigations. More explorations are needed to gain in-depth understanding of the biological function of DPP9 in tumor biology and the underlying mechanisms.
Johnson et al. also teach “In mouse myeloid cells, Dpp8/9 inhibition activates the inflammasome sensor Nlrp1b, which in turn activates pro-caspase-1 to mediate cell death3, but the mechanism of DPP8/9 inhibitor-induced pyroptosis in human myeloid cells is not yet known.” See abstract of Johnson et al.
Hence, in the absence of a showing of correlation between all the diseases claimed as capable of treatment and prevention by the administration of the compounds of the claims, one of skill in the art is unable to fully predict possible results from the administration of the compound of the present claims due to the unpredictability disclosed in the prior art.
The amount of direction or guidance present and The presence or absence of working examples
There are no working examples present for the prevention of any disease or disorder by administering an instantly claimed compound.
The only direction or guidance present in the present disclosure is the definitions of treatment located on page 8, lines 19-30. Applicant provides a listing and definitions of DPP9 enzyme-related disorders on page 26-27. Applicant teaches where the definition of treatment or prevention of a disease may comprise partial or complete remission (see page 8 of the instant disclosure). The DPP9 enzyme-related disorders largely presented are various cancer subtypes or proliferative diseases.
Applicant discloses a working example where compounds were biochemically evaluated against a panel consisting of all enzymatically active DASH enzymes (DPP4, DPP8, DPP9, DPP2, FAP) and PREP in pages 53-58. See also Table 1 on pages 54-55 and Table 2 on pages 57-58.
The disclosure does not provide how the in vitro data correlates to the treatment of any disease or disorder as claimed. The uses covered by the claims are not enabled based solely on the assay testing reported in the specification. Various studies are required to enable compounds in clinical development; for example, development routinely relies on animal models in addition to iterative assays, not assay testing as done herein. Note Hoffman V. Klaus 9 USPQ2d 1657 (1988) regarding the standard of testing that is necessary to establish the likelihood of in vivo use. Also see Ex parte Powers 220 USPQ 924 (1982) regarding the absence of animal studies and the absence of correlation between the studies conducted in vitro and the diseases to be treated. In the absence of sufficient testing of animal models, or any models otherwise for the correlation of DPP9 inhibition to the treatment and prevention of any DPP9 enzyme-related disorder, the claims are not enabled for a skilled artisan.
Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such area. Note as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
Regarding prevention, there is no evidence of record, which would enable the skilled artisan in the identification of the people who have the potential of becoming afflicted with the numerous diseases/disorders or conditions claimed herein.
That a single compound can be used to prevent all diseases/disorders and conditions embraced by the claim is an incredible finding for which Applicant has not provided supporting evidence. Applicant has not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use for preventing any or all of the diseases/disorders or conditions by administering the instant claimed compound.
The breadth of the claims
The breadth of claim 17 includes both the treatment and prevention of any disease or disorder comprising administering to a subject in need thereof a compound according to claim 1, which also comprises a compound of formula (I) and pharmaceutically acceptable salts thereof. Applicant teaches where the definition of treatment or prevention of a disease may comprise partial or complete remission (see page 8 of the instant disclosure). Applicant has placed no limitation in the claims or definition in the specification to limit the scope of the diseases and disorders encompassed by claim 17. Furthermore, the instant claims encompass the treatment and prevention of ‘cancer’, which is taken to encompass all forms and subtypes of cancer, for which there is no enablement provided.
Although applicant has included a limiting definition of the DPP9 enzyme-related disorder the instant composition is intended to treat or prevent, the breadth of claim 17 includes the treatment and prevention of any disease.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what diseases, disorders, or conditions out of all diseases, disorders, or conditions instantly claimed would be amenable to prevention in the first place, which would also require a person having ordinary skill in the art to establish methods of identifying subjects who do not currently have the various conditions but would otherwise develop them without intervention. Given that the state of the art establishes a lack of any known methods of reliable prevention for any and all disorders, a person having ordinary skill in the art would need to develop preventative approaches that have eluded entire fields of research for multiple different conditions. Such a task clearly extends beyond what can be considered routine experimentation.
The level of the skill in the art
The level of skill in the art is high; however, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro or in vivo screening to determine which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
The artisans making and using applicant’s pharmaceutical compositions would be a collaborative team of synthetic chemists and/or health practitioners, possessing commensurate degree level and/or skill in the art, as well as several years of professional experience.
One of skill in the art would not be able to make use of the present combination based on the in vitro and in vivo data present in a method of treating any disease or disorder.
The specification fails to provide sufficient support of the broad use of the compound of the instant claims for the treatment and prevention of any potential disease or disorder, necessitating one of skill to perform an exhaustive search for which diseases can be treated or prevented by what compounds of the present claims in order to practice the claimed invention.
Factors such as “sufficient working examples”, “the level of skill in the art” and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claim, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. {In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)}.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test which hyper-proliferative can be treated or prevented by the composition encompassed in the instant claim, with no assurance of success.
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 1-15 and 17-18 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.
Claim 1 recites the limitation of a compound of Formula I having the structure pictured below.
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The definition of Formula I includes where R comprises “-(alkyl-O)n-(CH2)-X”, which is indefinite as the variable X is not depicted in the structure of Formula I or defined elsewhere in the definition of a compound of Formula I.
One of ordinary skill in the art would not be sure if the alternative comprising X in the definition for R is superfluous or the structures provided are incomplete.
Claims 2-15 and 17-18, which are dependent upon claim 1, are also rejected.
Claim 12 recites the limitation “wherein said X moiety is selected from E3 ligase ligand moiety or from a molecular reporter moiety”, in lines 2-3 of present claim 12. The variable X is not defined in claim 1, and thus the limitation of claim 12 lacks antecedent basis.
Claim 13 recites the limitation “wherein X moiety of said compound engages with an E3 ubiquitin ligase”, in lines 1-2 of present claim 13. When claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Halliburton Energy Servs., Inc. v. M-I LLC, 514 F.3d 1244, 1255, 85 USPQ2d 1654, 1663 (Fed. Cir. 2008). See MPEP 2173.05(g).
In this instance, the claims are unclear because one of ordinary skill would not be appraised of which alternatives, or combination of alternatives, are required to meet the limitation of the claims.
Claim 14 recites the limitation "a reporter moiety" in line 2 of present cla. There is insufficient antecedent basis for this limitation in the claim. Claim 12, which claim 14 depends upon, recites “wherein said X moiety is […] a molecular reporter moiety”.
Claim 17 recites the limitation "a pharmaceutical composition according to claim 1" in lines 2-3. There is insufficient antecedent basis for this limitation in the claim. Claim 1 is directed to a compound of formula I.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10-14 are are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 recites where X is independently selected from
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. Claim 1 does not define the variable X, and thus the scope of claim 10 is not further limiting.
Applicant may define X in claim 1 according to the limitation provided in claim 10, to overcome this aspect of the rejection.
Claim 11 recites “The compound according to claim 1, wherein the compound is a DPP9 inhibitor”. The limitation of present claim 11, which is dependent upon claim 1, is not considered further limiting as it presumed that any compound of instant Formula I, which meets the requirements of claim 1, will have the required properties of claim 11.
Claims 12-14 recite definitions for the variable X, which is not defined in parent claim 1. As such the scope of claims 12-14 are broader than the claims from which they depend and are properly rejected.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
Claims 1-15 and 17-18 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to QUINCY A MCKOY whose telephone number is (703)756-4598. The examiner can normally be reached Monday - Thursday 8:00 - 6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/QUINCY A. MCKOY/
Patent Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626
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