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 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 23 is 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.
The rejected embodiments cover a glutaminyl-modified antibody.
To satisfy the written-description requirement, the specification must describe every element of the claimed invention in sufficient detail so that one of ordinary skill in the art would recognize that the inventor possessed the claimed invention at the time of filing. Vas-Cath, 935 F.3d at 1563; see also Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997) (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”); In re Gosteli, 872 F.2d 1008, 1012 (Fed. Cir. 1989) (“the description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed”).
With regard to the recited genus of antibodies, the following applies:
Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 94 USPQ2d 1161 (Fed. Cir. 2010) states that “...a generic claim may define the boundaries of a vast genus of chemical compounds...the question may still remain whether the specification, including the original claim language, demonstrates that the applicant invented species sufficient to support a claim to a genus”. See page 1171.
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, reduction to drawings, 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. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
See also 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 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.
Amgen, Inc. v. Chugai Pharmaceutical Co., Ltd., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991) states that “it is well established in our law that conception of a chemical compound requires that the inventor be able to define it so as to distinguish it from other materials, and to describe how to obtain it”.
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 structural features common to the members of the genus, which features constitute a substantial portion of the genus, so that one of skill in the art can “visualize or recognize” the members of the genus (Emphasis added). Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997).
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if 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.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B(i), the court states, "An adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention."
Courts have stated that “[i]n claims involving [non-genetic] chemical materials, generic formulae usually indicate with specificity what the generic claims encompass. One skilled in the art can distinguish such a formula from others and can identify many of the species that the claims encompass. Accordingly, such a formula is normally an adequate description of the claimed genus.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). (emphasis added).
There is no such specificity here, nor could one skilled in the art identify particular antibodies encompassed by the claims. To the contrary, the specification states that the claimed compounds are derived from the recited substituents. Specifically, Applicant fails to disclose any other antibodies, besides those prepared by the transglutaminase-mediated methods in the specification, and in relation to the above, these disclosed species do not represent the substantial variety covered by the genus of antibodies
The Examiner acknowledges that a working example or exemplified embodiment is not necessarily a requirement for description. However, where a generic claim term is present in a claim, as in the present application, and defined only by functional characteristics, the specification must convey enough information, e.g., via sufficient representative examples, to indicate invention of species sufficient to constitute the genus. Enzo Biochem, Inc. v. Gen-Probe Inc., 323 F.3d 956, 967 2 (Fed. Cir. 2002). The written description requirement “requires a description of an invention, not an indication of a result that one might achieve if one made that invention.” Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997); see also Novozymes A/S v. DuPont Nutrition Biosciences APS, 723 F.3d 1336, 1350 (Fed. Cir. 2013) (“A patent...‘is not a reward for the search, but compensation for its successful conclusion.’ ... For that reason, the written description requirement prohibits a patentee from ‘leaving it to the ... industry to complete an unfinished invention.’” (citations omitted)).
Accordingly, the specification lacks adequate written description for the recited glutaminyl-modified antibodies.
Claims 32 and 34 are 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 treatment of cancer with specific antibody-drug conjugates (ADC’s), does not reasonably provide enablement for treatment of any condition with an antibody that has been conjugated with the recited primary amine. 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.
“The standard for determining whether the specification meets the enablement requirement [in accordance with the statute] was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term "undue experimentation," it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). See also United States v. Telectronics, Inc., 857 F.2d 778, 785, 8 USPQ2d 1217, 1223 (Fed. Cir. 1988) ("The test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation."). A patent need not teach, and preferably omits, what is well known in the art. In re Buchner, 929 F.2d 660, 661, 18 USPQ2d 1331, 1332 (Fed. Cir. 1991); Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1384, 231 USPQ 81, 94 (Fed. Cir. 1986), cert. denied, 480 U.S. 947 (1987); and Lindemann Maschinenfabrik GMBH v. American Hoist & Derrick Co., 730 F.2d 1452, 1463, 221 USPQ 481, 489 (Fed. Cir. 1984). Determining enablement is a question of law based on underlying factual findings. In re Vaeck, 947 F.2d 488, 495, 20 USPQ2d 1438, 1444 (Fed. Cir. 1991); Atlas Powder Co. v. E.I. du Pont de Nemours & Co., 750 F.2d 1569, 1576, 224 USPQ 409, 413 (Fed. Cir. 1984).” See M.P.E.P. § 2164.
Here, the nature of the invention is preparing a antibody precursor that can be used to prepare ADC’s which are used to treat cancer. In this regard, determining how a particular antibody conjugate will impact the body is not routine and the level of ordinary skill in the art of disease etiology is high, as an ordinary artisan in this art needs specialized knowledge of pharmacology. Applicant is reminded of the heightened enablement for these types of inventions:
Specifically, the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The "amount of guidance or direction" refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. [I]n the field of chemistry generally, there may be times when the well-known unpredictability of chemical reactions will alone be enough to create a reasonable doubt as to the accuracy of a particular broad statement put forward as enabling support for a claim. This will especially be the case where the statement is, on its face, contrary to generally accepted scientific principles. Most often, additional factors, such as the teachings in pertinent references, will be available to substantiate any doubts that the asserted scope of objective enablement is in fact commensurate with the scope of protection sought and to support any demands based thereon for proof. [Footnote omitted.].
Therefore, either the state of the art or the specification needs to establish that the recited antibody-primary amine precursors.
In this relation, ADC’s comprising a tumor-specific antibody conjugated to a cytotoxic drug have been shown as effective against cancers.
Therefore, the use of ADC’s for treatment of cancer may be characterized as “known”, but use of ADC precursors for treatment of diseases, such as the instant primary amine precursors, is not predictable. For instance, there is no nexus between the use of these conjugates and treatment of diseases. Thus, it is unpredictable whether compound used for preparing ADC’s can also be used for treatment, since there doesn’t appear to be a link between cancer treatment and these conjugate precursors.
The specification fails to remedy the state of the art. Here the specification teaches preparing the precursors and using them for making ADC’s. The specification does not provide any additional examples or guidance on how to use the recited precursors for treating cancer. The prior art provides no compensatory guidance and it would require undue experimentation to practice the invention for prevention of diseases. The amount of experimentation would be undue because it would require determining how to use the precursors to treat diseases like cancer. Specifically, as outlined above, it is not routine to determine the complex pharmacology of antibodies. In the instant case, it is only known that the instant antibody, and its precursor conjugates, can be used to prepare ADC’s. This means that significant experimentation would be required to determine how these conjugates can be used to treat diseases. This is because those of ordinary skill in the art cannot extrapolate between the activity of the antibody precursors and treatment. Moreover, there is little guidance, in both the prior art and the specification, with respect to the use of such precursors to treat diseases.
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 31, 32 and 34 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 31 recites compositions comprising the antibody of claim 29, but claim 29 recites methods of preparing a glutaminyl-modified antibody. Therefore, the antibody of claim 31 lacks antecedent basis in claim 31.
Claim 32 recites methods of treating comprising administering the antibody of claim 29, but claim 29 recites methods of preparing a glutaminyl-modified antibody. Therefore, the antibody of claim 32 lacks antecedent basis in claim 31.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 23 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dennler et al., BIOOCONJUGATE CHEMISTRY, vol. 25, no. 3, 19 March 2014 (2014-03-19), pages 569-578 (Dennler).
Dennler teaches a glutaminyl-modified antibody. ADCs with a DAR of 2 were obtained. The ADCs disclosed in Dennler are suitable for therapy or for the treatment of cancer:
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The glutaminyl-modified antibody and ADC are depicted, below:
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The preparation steps do not further limit the recited antibody, see MPEP 2113 (“[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”).
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 § 2146 et seq. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1, 5-16, 21-32, 34, 64, 65, 93-95 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-32 of U.S. Patent No. 11786603
Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding instant claim 1, conflicting claim 1 recites a method of producing a glutaminyl-modified antibody comprising: (a) reacting, in a mixture, a deglycosylated antibody or aglycosylated IgG antibody, with at least 200 molar equivalents of a primary amine compound to provide at least a 97.5% drug occupancy relative to the number of sites available, according to the instant primary amine; in the presence of transglutaminase at a pH between 7.6±0.05 and 7.8±0.05 for at least 4 hr, wherein antibody is first added to the mixture, followed by primary amine, and finally transglutaminase, at a temperature between about 25° C. and about 40° C.
Regarding instant claims 5-8, conflicting claims 2-8 recite:
- that the primary amine compound of step (a) is at a concentration of at least 50 molar equivalents compared to the deglycosylated antibody or aglycosylated antibody.
- wherein the primary amine compound of step (a) is at a concentration of at least 100 molar equivalents compared to the deglycosylated antibody or aglycosylated antibody.
- wherein the primary amine compound of step (a) is at a concentration of at least 200 molar equivalents compared to the deglycosylated antibody or aglycosylated antibody.
- wherein the transglutaminase of step (a) is present at 1 to 30 U per milligram of deglycosylated antibody or aglycosylated antibody.
- wherein the transglutaminase of step (a) is present at least at 2.5 U per milligram of deglycosylated antibody or aglycosylated antibody.
- wherein the transglutaminase of step (a) is present at least at 10 U per milligram of deglycosylated antibody or aglycosylated antibody.
- wherein the transglutaminase of step (a) is present at about 25 U per milligram of deglycosylated antibody or aglycosylated antibody.
Regarding instant claims 9-11, conflicting claims 10-11 recite:
- that the reaction of step (a) is at a pH of 7.6±0.05.
- wherein the reaction of step (a) is at a pH of 7.7±0.05.
- wherein the reaction of step (a) is at a pH of 7.8±0.05.
Claim 12-16, 21-32, 34, 64, 65, 93-95, the conflicting claims recite:
12. The method of claim 1, wherein the transglutaminase of step (a) is a microbial transglutaminase.
13. The method of claim 1, wherein step (a) is conducted for at least 18 hours.
14. The method of claim 1, wherein step (a) is conducted for at least 24 hours.
15. The method of claim 1, wherein the antibody is deglycosylated with peptide N-glycosidase F (PNGaseF) prior to step (a).
16. The method of claim 1, wherein the antibody is aglycosylated.
17. The method of claim 1, wherein step (a) is conducted in one or more solvent(s) selected from the group consisting of water, buffered water, saline water, buffered saline water, and an organic solvent.
18. The method of claim 1, wherein step (a) is conducted in water buffered with phosphate, HEPES, or MOPS.
19. A glutaminyl-modified antibody produced by the method of claim 1.
20. The method of claim 1, further comprising: (b) purifying the glutaminyl-modified antibody via affinity chromatography or protein A chromatography.
21. The method of claim 20, further comprising (c) reacting the glutaminyl-modified antibody with a reactive payload compound to form an antibody-payload conjugate.
22. The method of claim 20, further comprising (c) reacting the glutaminyl-modified antibody with a reactive linker-payload compound to form an antibody-linker-payload conjugate.
23. The method of claim 20, further comprising (c) reacting the glutaminyl-modified antibody with a reactive linker compound to form an antibody-linker conjugate; and (d) reacting the antibody-linker conjugate with a reactive payload compound to form an antibody-linker-payload conjugate.
24. The method of claim 1, that provides less than 10% side product, relative to desired antibody conjugates.
25. A pharmaceutical composition comprising the antibody of claim 1 and one or more pharmaceutically acceptable diluents, excipients, or carriers.
26. A method of treating a condition in a subject in need thereof comprising administering to the subject a pharmaceutically acceptable amount of the antibody of claim 1.
27. The method of claim 26, wherein the condition is cancer.
28. The method of claim 1, wherein the antibody comprises a modification at HC Q295.
29. The method of claim 1, wherein the antibody comprises a HC N297Q modification.
30. A method of producing a glutaminyl-modified antibody comprising: (a) reacting in a mixture a deglycosylated antibody or aglycosylated IgG antibody, with at least 200 molar equivalents of a primary amine compound to provide a DAR of at least 4.0, according to the instant primary amine in the presence of transglutaminase at a pH between 7.6±0.05 and 7.8±0.05 for at least 4 hr, wherein antibody is first added to the mixture after, followed by primary amine, and finally transglutaminase at a temperature between about 25° C. and about 40° C.
31. The method of claim 1, wherein the reaction of step (a) is between pH of 7.6 to 7.8.
32. The method of claim 30, wherein the reaction of step (a) is between pH of 7.6 to 7.8.
Based on the above, the conflicting claims the recite the elements of the claimed invention with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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