Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions. Claims 1, 10-14 and 26 are pending in this application.
Claimed Priority
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Specification Objection - Title
Applicant is reminded of the proper content of the title of the invention.
The title of the invention should be brief, but technically accurate and descriptive. See 37 CFR 1.72(a) and MPEP § 606. The title of the invention should be more descriptive of what is claimed.
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.
Claims 1, 10-14 and 26 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 full scope of the claimed invention. This is a written description rejection. Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1st "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurkar, 19 USPQ2d 1111, states that 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 courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.
The reaction of claims 1, 10-14 encompasses any type of reactions steps and conditions (including chemical and biochemical reactions) to covalently link an “effector or reporter molecule” of any structure to any bifunctional linker of any structure and to conjugate this to a cell-binding agent of any structure, in any way. As a result, the product claimed in claim 26 is any conjugate which comprises an effector or a reporter molecule linked to a cel binding agent. Claims 1, 10-14 and 26 do not provide the necessary chemicals and conditions to practice the claimed process. There are no structural characteristics described for the effector or reporter molecule, for the linker and the cell-binding agent. It is noted that in the specification the effector or reporter molecule of step (a) is required to have certain specific characteristics (e.g., a thiol group, being a maytansinoid) to practice the chemical process, and the bifunctional linker reagent is required to have certain specific structural characteristics to practice the “conjugation” process of step (b). The specification discloses examples of working reaction conditions but only with those required characteristics that are currently lacking in the rejected claims. The state of the art is that “chemical reactions are known as unpredictable”. In re Marzocchi, et al., 169 USPQ 367, 370 (CCPA 1971); In re Fisher, 166 USPQ 18, 24 (CCPA 1970). Here, the unpredictability comes from when there is no limitation to what reagents should be used and what the reaction parameters are. Hence, the need for greater disclosure.
“The examples and description should be of sufficient scope as to justify the scope of the claims”. See MPEP § 608.01(p). If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, para. 1 (MPEP 2163).
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In accordance with the "Supplementary Examination Guidelines for Determining Compliance with 35 U.S.C. 112 and for Treatment of Related Issues" (76 Fed. Reg. 7162):
“Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C. 112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197..”
A similar issue arises in claims 1, 10-14 and 26. Claims 1 and 10-14 cover every conceivable means for achieving the stated result. However, the specification discloses only those means known to the inventor, which is not commensurate in scope with the claims.
Accordingly, it is deemed that the specification does not describe in sufficient detail the genus in the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
In addition, where, as here, the claims cover a broad genus, 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” per MPEP 2163, or by the establishment of “a reasonable structure-function correlation.” AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
A "representative number of species" must represent the entire claimed genus and account for variation between the species of the genus.
[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. Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004).
What the instant claims cover is discussed above. The few species described in the specification cannot possibly represent the entire genus claimed or account for all of the variation between species of such a genus.
Chemistry and biotechnology are generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Carleton, 599 F.2d 1021, 202 USPQ 165, 170 (CCPA 1979) ("Although there is a vast amount of knowledge about general relationships in the chemical arts, chemistry is still largely empirical, and there is often great difficulty in predicting precisely how a given compound will behave.”). The pharmaceutical art, that is the use of a chemical compound to affect a desired physiological activity, is generally considered to be unpredictable and/or have unpredictable factors. See, e.g., In re Fisher, 427 F.2d 833, 839 (CCPA 1970) (“In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved (emphasis added); In re Bowden, 183 F.2d 115, 86 USPQ 419, 423 (“chemical reactions frequently are unpredictable”).
Considering the unpredictability found in chemistry and biotechnology, accordingly, when a claim presents a genus with substantial variation as that currently presented by Applicant, the disclosure must adequately reflect such variation with a representative number of species. The lack of any disclosure of examples may be considered in determining whether a claimed invention was adequately described. Boston Scientific Corp. v. Johnson & Johnson, 647 F.3d 1353 (Fed. Cir. 2011).
The species described in the specification do not cover the entire genus such that it is a representative sample of the genus as the species are close together in structure and only describe an extremely small portion of the claimed genus. Therefore, the claims lack written description and are properly rejected under 35 U.S.C. 1121st (or 112(a)).
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a) the invention was known or used by others in this country, or patented or described in a printed publication in this or a foreign country, before the invention thereof by the applicant for a patent.
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim 26 is rejected under pre-AIA 35 U.S.C. 102(b) as being clearly anticipated by Chari et al. (US Patent 6,441,163).
Claim 26 is a product-by-process claim, however, patentability is based on the product itself. If the product is the same as a product from the prior art, the claim is unpatentable. See MPEP 2113:
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Chari teaches compositions comprising a purified conjugate in solution wherein the conjugate comprises an effector or reporter molecule lined to a cell binding agent. See at least Examples 1a, 1b and 5.
Claim Rejections - 35 USC § 103
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 35 U.S.C. 103(a) 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.
Claims 1, 10-14 and 26 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chari et al. (US Patent 6,441,163) in view of Polson et al. (Blood, 15 July 2007, Vol. 110 (2), p. 616-623) and Ebens et al. (US 2008/0050310).
Polson et al. teach the antibody-drug conjugate anti-CD79 (SN8)-MCC-DM1 made by the process of first reacting the antibody with the cross-linking reagent Succinimidyl-4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (SMCC) to produce MCC-antibody. The MCC-modified antibody was purified and equilibrated by treating with a buffer. In a second step, DM1, which is a reactive maytansinoid having a thiol group, is added to the MCC-modified antibody, resulting in the production of the DM1-modified antibody conjugate anti-CD79 (SN8)-MCC-DM1 (p. 617, left column, last paragraph).
Chari et al. teach a process for the production of cytotoxic conjugates of maytansinoids modified with a thiol group and cell binding agents. Maytansinoids having a disulfide linker that bears a reactive moiety are linked to cell binding agents, such as antibodies, without prior modification of the cell binding agent (antibody). Most of the methods use DM1 (col. 6 lines 63-66). Representational cytotoxic conjugates are antibody/maytansinoid, antibody fragment (e.g. Fab)/maytansinoid, epidermal growth factor (EGF)/maytansinoid, monoclonal anti-B4/maytansinoid, estrogen/maytansinoid, and huN901/maytansinoid (col. 9, lines 55-67, col. 10, lines 1-53 and Examples). At col. 3, lines 37-60, Chari discussed the advantages of their method over the prior art methods because “current methods of conjugation of maytansinoids with cell binding agents (such as antibodies) involve two reaction steps. A cell binding agent, for example an antibody, is first modified with a cross-linking reagent such as N-succinimidyl pyridyldithiopropionate (SPDP) to introduce dithiopyridyl groups into the antibody. In a second step, a reactive maytansinoid having a thiol group, such as DM1, is added to the modified antibody, resulting in the displacement of the thiopyridyl groups in the modified antibodies, and the production of disulfide-linked cytotoxic maytansinoid/antibody conjugates”. Thus “the current methods of conjugation of maytansinoids with antibodies suffer from the drawbacks of subjecting antibodies to two reaction steps, thus requiring two protein purification steps of gel-filtration to separate the proteins from unconjugated small organic molecules such as SPDP and maytansinoids. This makes the methods expensive and time consuming, and also results in low product yield”. Thus, Chari teaches not to subject the cell binding agent (e.g. antibody) to two reaction steps, and this is done by first making the modified maytansinoid containing the linking moiety that has a reactive group (such as in Figure 3), and second, reacting the cell binding agent (e.g. antibody) with the modified maytansinoid containing the linking moiety that has a reactive group to produce cytotoxic conjugates (such as in Figure 4) (also col. 5, lines 44-46, col. 6,lines 21-48, col. 7, lines 26-29). The pH of the conjugation to the cell binding agents (antibody) is between 6-8 (col. 4, lines 15-20).
Ebens teaches maytansinoid-antibody conjugates with DM1 or DM4 and SMCC linker (para. [0114], [0122]-[0124]) and also with GMBS as linker (para. [0766], [0907] Example 8). See also Example 11.
Ascertainment of the Difference Between the Prior Art and the Claims
(MPEP §2141.012)
The difference between instant claims and the prior art is that the order of reaction steps of Polson is reversed (as in Chari). The difference with Example 8 (para [0907]) of Ebens is that Ebens doesn’t specify how the effector having linkers bound thereto (maytansinoid-linker) mixture was prepared.
Finding of prima facie obviousness--rational and motivation (MPEP §2142-2413)
The person of ordinary skill in the art is a person who knows the relevant art at the time of the invention. MPEP 2141.03. Such a person will employ "inferences and creative steps." KSR at 418, 82 USPQ2d at 1396. The Supreme Court has held that "[a] person of ordinary skill is also a person of ordinary creativity, not an automaton." KSR International Co. v. Teleflex INc. 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007).
It would have been prima facie obvious to one of ordinary skill in the art to make the DM1-modified antibody conjugate of Polson by the process steps order of Chari (as in Fig. 3 and 4 of Chari), because Chari taught the benefits (discussed above) of reversing the order of the process steps in the same reactions to make similar maytansinoid cytotoxic conjugates modified with a thiol group and cell binding agents. In addition, MPEP 2144.04 (IV) C. supports the examiner’s conclusion that reversing the order of the prior art process steps is prima facie obvious in the absence of new or unexpected results.
It is noted that Ebens has the same order of process steps and Chari. It would have been prima facie obvious to one of ordinary skill in the art to make the DM4-modified antibody conjugates of Ebens, by the process steps order of Chari (as in Fig. 3 and 4 of Chari), because Chari taught the benefits (discussed above) of the order of the process steps in the same reactions to make the same maytansinoid cytotoxic conjugates modified with a thiol group and cell binding agents.
In an effort of reducing the purification steps, as encouraged by Chari et al., a skilled artisan would have known to react the cross-linker of the references first with one of the reagents in conditions that favor total use of the cross-linker (i.e. excess of either antibody or maytansinoid) and after that adding the second reagent to the intermediary product. Thus, performing the order steps of Chari and Ebens (in Example 8, para [0907]) for avoiding to subject the antibody to two reaction steps, the artisan is left with only one practical possibility for reducing the purification steps, namely react the maytansinoid (which contains a free sulfhydryl but no free amine group) in conditions that the maytansinoid is in molar excess and thus consuming all the maleimide groups. Such an intermediary product would not need separation from the reaction mixture because, in the second step, after adding the antibody, the only reactive group would be the NHS and it would react with free amines on the antibody. This rationale is totally within the grasp of an ordinary artisan and since the claims are so broad that no specific reaction conditions are present, there is nothing unexpected and it could be obtained with a reasonable expectation of success by any research chemist tasked with obtaining the conjugates in one-step reaction for the reasons underscored by Chari et al. and Ebens
Thus claims 1, 10-14 and 26 are obvious over the prior art cited in view of the routine knowledge in the art at the time that the invention was made.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 16-18 and 20-22 of U.S. Patent No. 9,771,432. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-14, 16-18 and 20-22 of the patent anticipate the instant claims. They teach the same process in the same order as claimed herein, presenting 3 bifunctional linker reagents, an effector and the cell binding agent (particularly claims 6, 9 and 13). They provide the same product of claim 26.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 and 16-30 of U.S. Patent No. 9,376,500. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-14 and 16-30 of the patent anticipate the instant claim. They teach the same process in the same order as claimed herein, presenting the bifunctional linker reagent, an effector molecule and a cell binding agent. They provide the same product of claim 26.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 8,624,003. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-13 of the patent anticipate the instant claim. They teach the same process in the same order as claimed herein, presenting the bifunctional linker reagent, an effector molecule and a cell binding agent. They provide the same product of claim 26.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10,233,257. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-15 of the patent anticipate the instant claim. They teach the same process in the same order as claimed herein, presenting the bifunctional linker reagent, an effector molecule and a cell binding agent. They provide the same product of claim 26.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,815,309. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-19 of the patent anticipate the instant claim. They teach the same process in the same order as claimed herein, presenting the bifunctional linker reagent, an effector molecule and a cell binding agent. They provide the same product of claim 26.
Claims 1, 10-14 and 26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11,498,979. Although the claims at issue are not identical, they are not patentably distinct from each other because claims 1-16 of the patent anticipate the instant claim. They teach the same process in the same order as claimed herein, presenting the bifunctional linker reagent, an effector molecule and a cell binding agent. They provide the same product of claim 26.
Conclusion
Claims 1, 10-14 and 26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to VALERIE RODRIGUEZ-GARCIA whose telephone number is (571)270-5865. The examiner can normally be reached Monday-Friday 9:30am-5:30pm.
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/VALERIE RODRIGUEZ-GARCIA/ Primary Examiner, Art Unit 1621
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