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 24-27, and 36 have been amended. Claims 49-54 have been added. Claims 24-42 and 44-54 are pending and under consideration to the extent that they encompass the elected species (vi) of formula II, wherein the toxin is linked to the cell binding agent through conjugation at position R10 together with R11..
The rejection of claims 24, 25 and 36 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention is withdrawn in light of applicant’s amendments of the claims to remove reference to Tradenames.
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 49-54 are rejected and claims 24-42 and 44-48 remain 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.
Section 2163 of the M.P.E.P. states that 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, 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 applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
Applicant has reduced to practice the amanita toxin drug linkers 71, 145, 111, 152, 153, 166, 195, 196, 213, 214, 215, 239, S-1 and S-2. It is noted that in all the examples, with the exception of “71” the core structure is identical, the difference being in the linker structures. Compound 71 differs from compounds 145, 111, 152, 153, 166, 195, 196, 213, 214, 215, 239, S-1 and S-2 in having an R5 of OH rather than NH2 and a X of S rather than SO. However, the core structures claimed are highly variant encompassing R.sub.1 and R.sub.2 are independently selected from H, OH, CH.sub.2OH, CH(OH)CH.sub.2OH, CH(CH.sub.3)CH.sub.2OH, CH(OH)CH.sub.3, C.sub.1-C.sub.8 alkyl, —OR.sub.12 (ether), C.sub.2-C.sub.8 alkenyl, alkynyl, heteroalkyl, —OCOR.sub.12 (ester), —OC(═O)OR.sub.12 (carbonate), —OC(═O)NHR.sub.12(carbamate); C.sub.3-C.sub.8 aryl, heterocyclic, carbocyclic, cycloalkyl, heterocycloalkyl, heteroaralkyl, alkylcarbonyl; R.sub.3 and R.sub.4 are independently selected from H, OH, —OR.sub.12 (ether), —OCOR.sub.12 (ester), —OCOCH.sub.3 (acetate), —OCOOR.sub.12 (carbonate), —OC(═O)NHR.sub.12(carbamate), —OP(O)(OR.sub.12)(OR.sub.12′) (phosphate), OP(O)(NHR.sub.12)(NHR.sub.12′) (phosphamide), O—SO.sub.3.sup.−, or O-glycoside; R.sub.5 is selected from H, OH, NH.sub.2, NHOH, NHNH.sub.2, —OR.sub.12, —NHR.sub.12, NHNHR.sub.12, —NR.sub.12R.sub.12′, or N(H)(R.sub.12)R.sub.13CO(Aa).sub.p, (an amino acid or peptide), wherein Aa is an amino acid or a polypeptide, p represents 0-6; R.sub.6 is selected from H, OH, CH.sub.2OH, CH(OH)CH.sub.2OH, CH(CH.sub.2OH).sub.2, CH(CH.sub.3)OH, CH.sub.2CH.sub.2OH, PrOH, BuOH, C.sub.1-C.sub.8 alkyl, —OR.sub.12 (ether), C.sub.2-C.sub.8 alkenyl, alkynyl, heteroalkyl, —OCOR.sub.12 (ester); C.sub.3-C.sub.8 aryl, heterocyclic, or carbocyclic; R.sub.7, R.sub.8 and R.sub.9 are independently selected from H, OH, CH.sub.3, CH(CH.sub.3).sub.2, CH (CH.sub.3)CH.sub.2CH.sub.3, CH.sub.2OH, CH(OH)CH.sub.2OH, CH.sub.2CH(OH)CH.sub.2OH, CH(CH.sub.2OH).sub.2, CH.sub.2C(OH)(CH.sub.2OH).sub.2, CH.sub.2C(OH)(CH.sub.3)(CH.sub.2OH), CH.sub.2C(OH)(CH(CH.sub.3).sub.2)(CH.sub.2OH), CH.sub.2CH.sub.2OH, PrOH, BuOH, CH.sub.2COOH, CH.sub.2CH.sub.2COOH, CH(OH)COOH, CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2CONH.sub.2, CH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2, CH.sub.2CH.sub.2CH.sub.2NHC(═NH)NH.sub.2, C.sub.1-C.sub.8 alkyl, CH.sub.2Ar, CH.sub.2SH, CH.sub.2SR.sub.12, CH.sub.2SSR.sub.12, CH.sub.2SSAr, CH.sub.2CH.sub.2SCH.sub.3, —OR.sub.12(ether), C.sub.2-C.sub.8 alkenyl, alkynyl, heteroalkyl, —OCOR.sub.12 (ester); C.sub.3-C.sub.8 aryl, heterocyclic, or carbocyclic and wherein “X” is S, O, NH, SO, SO2 or CH2. Further, the linker structures represented in compounds 71, 145, 111, 152, 153, 166, 195, 196, 213, 214, 215, 239, S-1 and S-2 do not describe the genus of linker structures encompassed by the claims wherein L.sub.1 and L.sub.2 are, the same or different, and are independently selected from O, NH, N, S, P, NNH, NHNH, N(R.sub.3), N(R.sub.12), N(R.sub.12)N(R.sub.12), CH, CO, C(O)NH, C(O)O, NHC(O)NH, NHC(O)O, a polyethyleneoxy unit of formula (OCH.sub.2CH.sub.2).sub.pOR.sub.12, (OCH.sub.2CH—(CH.sub.3)).sub.pOR.sub.12, NH(CH.sub.2CH.sub.2O).sub.pR.sub.12, NH(CH.sub.2CH(CH.sub.3)O).sub.pR.sub.12, N[(CH.sub.2CH.sub.2O).sub.pR.sub.12]—[(CH.sub.2CH.sub.2O).sub.pR.sub.12], (OCH.sub.2CH.sub.2).sub.pCOOR.sub.12, or CH.sub.2CH.sub.2(OCH.sub.2CH.sub.2).sub.pCOOR.sub.12, wherein p and p′ are independently an integer selected from 0 to about 1000, or a combination of two or more of above; C.sub.1-C.sub.8 alkyl; C.sub.2-C.sub.8 heteroalkyl, alkylcycloalkyl, heterocycloalkyl; C.sub.3-C.sub.8 aryl, Ar-alkyl, heterocyclic, carbocyclic, cycloalkyl, heteroalkylcycloalkyl, alkylcarbonyl, heteroaryl; or (Aa).sub.r, r=1-12 (one to 12 amino acid units), which is composed from natural or un-natural amino acids, or a same or different sequence of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit, or formula I-q1, wherein Q.sub.1, Q.sub.2, L.sub.1, L.sub.2, V.sub.1, or V.sub.2, can be independently absent but Q.sub.1 and Q.sub.2 are not absent at the same time; V.sub.1 and V.sub.2 are independently a spacer unit selected from O, NH, S, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 heteroalkyl, alkenyl, alkynyl, C.sub.3-C.sub.8 aryl, heterocyclic, carbocyclic, cycloalkyl, alkylcycloalkyl, heterocycloalkyl, heteroaralkyl, heteroalkylcycloalkyl, or alkylcarbonyl, or (Aa).sub.r, r=1-12 (one to 12 amino acid units), which is composed from a natural or unnatural amino acid, or a same or different sequence of dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide or dodecapeptide unit; or (CH.sub.2CH.sub.2O).sub.p, p is 0-1000; v.sub.1 and v.sub.2 are independently 0, 1 or 2, but v.sub.1 and v.sub.2 are not 0 at the same time; n is 1 to 30.
Written description issues may arise if the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed product arising from the disclosed process (Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list" disclosure of every possible moiety does not necessarily constitute a written description of every species in a genus because it would not "reasonably lead" those skilled in the art to any particular species; MPEP 2162.1(A)).
Further, the criteria for a “representative number of species” to be described requires that the species which are reduced to practice are representative of the entire genus. The description of the conjugates reduced to practice with only a limited number of moieties of “R” groups attached to the core structure are not representative of the compounds required in the instant claimed conjugates and thus, it cannot be concluded that the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.").
Regarding the description of the genus by partial structure combined with a specific function, the specification fails to provide such a correlation. It would be expected that the plethora of different linkers having different formats attached to different parts of the amanita molecule would provide conjugates with different properties the drug being delivered with different kinetics under different microenvironmental conditions. It would also be expected that the released linkers would not in all cases provide the free drug (Casi and Neri, Journal of Controlled Release, 2012, Vol. 161, pp. 422-428, see Table 2). Thus, the resulting drug would be modified by the residue of the linker which can affect the toxicity or behavior of the drug.
The compounds described in the specification do not provide a description of
(i) all the compounds having the numerous linkers that could be generated from all the variables recited in the instant claims pertaining to the linkers,
(i) all the modifications of the amanita toxin core encompassed by the instant claims, and
(iii) the amanita toxin -linker structures attached to the large genus of cell-binding agents, T.
Thus, the specification fails to provide adequate written description for the genus of compounds claimed and does not reasonably convey to one of skill in the art that he inventors, at the time the application was filed, had possession of the genus of conjugates, methods of making said conjugates and pharmaceutical composition comprising said conjugates.
Applicant argues that the recent decision in Teva Pharmaceuticals v Eli Lilly pertains to the instant rejection because. In Teva Pharmaceuticals v Eli Lily the Court distinguished between claims to a genus and claims to a known genus. The Court determined that the disclosure of a specific example of the humanized anti-CGRP antibody was an adequate written description for purpose of that claimed invention which was a method of reducing or treating headache in a human. This has been considered but not found persuasive. The instant claims are drawn to a multitude of previous unknown amanita analogs. Any R group, X group, alteration in the size of the ring (m=0 or1), or combinations thereof is an analog. In the Teva Pharmaceuticals case, the prior art provided the other members of the genus of anti-CGRP antagonists. In the instant case, the prior art does not provide a description of a genus of
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wherein T is the cell binding agent ; Q1and Q2 are:
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and D is
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All claims are rejected/
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
