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 .
Claim Status
Claims 1-2, 4-6, and 8-18 are pending. Claims 4-5 and 10-18 are withdrawn. Claims 1-2, and 9 are rejected. Claims 6 and 8 are objected to.
Response to Amendment
Applicant’s amendments have overcome the previously presented rejections.
Election/Restrictions
As per MPEP 803.02, the examiner will determine whether the entire scope of the claims is patentable. Applicant’s elected species appears free of the art. Therefore, according to MPEP 803.02: should the elected species be found allowable, the examination of the Markush-type claim will be extended. Examination of the Markush-type claims has been extended to include the scope of claims 1-2, 6, and 8-9 of which claims 1-2 and 9 are not allowable under 35 USC §112. Any subject matter discussed outside this scope is presented in the interest of compact prosecution.
Claims 4-5 and 10-18 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
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 1-2 and 9 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim Scope (MPEP 2163(II)(A)(1))
MPEP 2163 outlines the methodology for determining adequacy of written description. MPEP 2163(II)(A)(1) instructs “For Each Claim, Determine What the Claim as a Whole Covers”.
The instant claims are directed to phospholipid ether conjugates as cancer-targeting drug vehicles wherein Z of instant formula (I) represents the cancer-targeting drug. Instant claim 5 (withdrawn) lists several species of auristatin antineoplastic agents for Z; claim 6 (withdrawn) recites compounds wherein Z is a combretastatin A-4 analog; and claim 8 recites species of compounds wherein Z is one of the specific PLK-1 inhibitors, combretastatin A-4 analogs, or auristatins listed in the “Determination of Sufficient Support” section below. However, the instant claims broadly are generic to the structural requirements of the many antineoplastic/cancer-targeting compounds represented by variable Z.
Additionally, claim 9 is directed to a pharmaceutical composition comprising the claimed compound and withdrawn claims 10-18 are directed to methods of treating cancer comprising administering a compound of claim 1.
Disclosed Support (MPEP 2163(II)(A)(2))
MPEP 2163(II)(A)(2) instructs “Revise the Entire Application to Understand How Applicant Provides Support for the Claimed Invention Including Each Element and/or Step”. The specification discusses the field of endeavor and states:
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The specification recites the individual species of PLK-1 inhibitors (paragraph [00080]), auristatins (paragraph [00081]), and combretastatin A-4 analog (paragraph [00083]) used in dependent claims 5, 6 and 8, and lists a number of other anti-cancer drugs of various classes (paragraph [00078]).
As further noted in MPEP 2163(II)(A)(2), “Such a review is conducted from the standpoint of one of ordinary skill in the art at the time the application was filed (see, e.g., Wang Labs., Inc. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art.” In this situation, the classes of antineoplastic agents in claim 1 present with incredible breadth whereas the representative examples provided are far narrower.
Regarding tubulin polymerase inhibitors, antimitotic agents and combretastatin A-4 analogs, Seddigi et al. discuss (title) “[r]ecent advances in combretastatin based derivatives and prodrugs as antimitotic agents” ((2017). Recent advances in combretastatin based derivatives and prodrugs as antimitotic agents. MedChemComm, 8(8), 1592–1603.). The prior art reports several tubulin polymerization inhibitors and states (page 1594):
The increased burden of cancer, toxicity of chemotherapeutic agents and resistance to anticancer drugs have driven the scientific community to develop newer and more potent cancer therapeutic drugs.7 In this regard, leads obtained from natural products have inspired medicinal chemists to
develop both natural product hybrids and synthetic molecules in the area of drug discovery. Some of the natural tubulin depolymerisation inhibitors include paclitaxel 1, epithilone 2, and discodermolide 3 which bind to the taxane domain of tubulin. On the other hand, natural tubulin polymerization inhibitors such as vincristine 4 and vinblastine 5 bind
to the vinca domain. Colchicine 6 and combretastatins (like CA-4) 7 are also natural tubulin polymerisation inhibitors; however they bind to the colchicine binding site (Fig. 2).
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Regarding dolastatins and auristatin antineoplastic agents Akaiwa et al. report (abstract; (2020). Antibody-Drug Conjugate Payloads; Study of Auristatin Derivatives. Chemical & pharmaceutical bulletin, 68(3), 201–211. Released on J-STAGE March 01, 2020):
Auristatins are important payloads used in antibody drug conjugates (ADCs), and the most well-known compound family member, monomethyl auristatin (MMAE), is used in two Food and Drug Administration
(FDA)-approved ADCs, Adcetris® and Polivy®. Multiple other auristatin-based ADCs are currently being evaluated in human clinical trials and further studies on this class of molecule are underway by several academic and industrial research groups.
The prior art identifies auristatins as synthetic derivatives of dolastatin and teaches (pages 203):
Dolastatin 10 (6) was advanced to a number of clinical studies for a variety of cancers; however, no significant clinical activity was observed at the maximum dose tolerated.35–42) The same result was obtained for water-soluble dolastatin analogs, the auristatin TZT-1027 (auristatin PE, 7b)43) (Fig. 2). As a further study to improve in vivo efficacy, new auristatin derivatives were developed, resulting in MMAE (7d) and MMAF (7e) (Fig. 2), which contain a functional handle for attachment of covalent linkers. An approach was developed to increase the therapeutic index of these compounds in clinical trials where MMAE and MMAF would be combined with a linker and cancer target-specific monoclonal antibodies as ADCs.44–49) The mechanism of action of auristatins is well suited for use in ADCs because they arrest tumor cells and at the same time are known to stimulate an immune response toward cancer cells by inducing immunogenic cell death.49) Several auristatins are used in ADCs including MMAE (7d),44–46) MMAF (7e),47) and a 2-aminoisobutyric acid auristatins derivative (PF-06380101, 7f).48) These fully synthetic dolastatin 10 derivatives should have a manufacturing advantage when compared with other ADC payloads, which are derived from natural product isolated sources.49)
Regarding PLK-1 inhibitors Gutteridge et al. report (abstract, (2016). Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics. Molecular cancer therapeutics, 15(7), 1427–1435.
Polo-like kinase 1 (Plk1) overexpression has been shown to occur in a wide range of tumors, prompting research and development of Plk1 inhibitors as a means of cancer treatment. This review discusses recent advances in the development of Plk1 inhibitors for cancer management.
In Table 1 (page 18), the prior art discloses several PLK-1 inhibitors being implemented in clinical trials as shown below:
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As shown, broad structural variability exists among PLK-1 inhibitors and tubulin polymerization inhibitors of which include combretastatin A-4 analogs.
Determination of Sufficient Support (MPEP 2163(II)(A)(3))
MPEP 2163(II)(A)(3) instructs “Determine Whether There is Sufficient Written Description to Inform a Skilled Artisan That Inventor was in Possession of the Claimed Invention as a Whole at the Time the Application Was Filed”. This section of the MPEP further provides the following guidance:
Possession may be shown in many ways. For example, possession may be shown by describing an actual reduction to practice of the claimed invention. Possession may also be shown by a clear depiction of the invention in detailed drawings or in structural chemical formulas which permit a person skilled in the art to clearly recognize that inventor had possession of the claimed invention. An adequate written description of the invention may be shown by any description of sufficient, relevant, identifying characteristics so long as a person skilled in the art would recognize that the inventor had possession of the claimed invention.
In this situation and as discussed above, Applicant has specifically disclosed the following antineoplastic agents for the instant claimed compound: monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and monomethyl auristatin E-D (MMAD); combretastatin A-4 analogs such as
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; and PLK-1 inhibitors such as
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MPEP 2163 (II)(A)(3)(a)(ii) discusses support for a generic claim as follows:
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus (see i)(C) above).
The same section notes the following:
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
In this situation, the many compounds embraced by tubulin polymerase inhibitors, tubulin stabilizers, eukaryotic translation initiation factor 4 (EIF4) inhibitors, and antineoplastic agents selected from the group of alkylating agents, antimetabolites, antitumor antibiotics, antimitotic agents, topoisomerase inhibitors, and dolastatins is beyond the scope of compounds that Applicant has sufficiently disclosed. The instant claims broadly are generic to any and all of these possible permutations comprising anti-neoplastic agents (Z) of these classes as they require no specific structural features. Applicant has failed to provide “disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus.” As such, the instant disclosure does not inform a person of ordinary skill on the various ways in which one may seek to prepare phospholipid ether conjugate.
Dependent claims 2, and 9 are rejected as lacking written description for the same reasons since they also encompass the unsupported scope of compounds of instant claim 1.
Allowable Subject Matter
Claims 6 and 8 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/A.A.C./Examiner, Art Unit 1626
/MATTHEW P COUGHLIN/Primary Examiner, Art Unit 1626
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