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 .
The preliminary amendments of 01/29/2024 have been entered in full. Claims 1, 8, 10, 12, 14, 15, 21-23, 25, 27, 29, 30, 37, 39, 40, 44-46, 48, 50, and 52 are pending and under consideration.
Specification
The disclosure is objected to because of the following informalities: The structures depicted on pages 2 and 7 of the specification and in claims 25 and 48 are illegible.
Appropriate correction is required.
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 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, 8, 10, 12, 14, 15, 21-23, 25, 27, 29, 30, 37, 39, 40, 44-46, 48, 50, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 11661438. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons.
Patented claim 1 is drawn to a method comprising loading an antibody drug conjugate (ADC) preparation onto a hydroxyapatite column followed by washing the column with 5-35 mM sodium phosphate buffer and eluting the ADC with a sodium phosphate buffer of gradually increasing concentration up to about 140 mM. This patented method is a species of the generic methods of pending claims 1 and 30, which recite the same steps but broadly recite that the concentrations of sodium phosphate are “low” and “gradually increasing” (claim 1) or “low” and “high” (claim 30), without reciting any specific concentrations. Pending dependent claims 14, 15, 39, and 40 recite sodium phosphate concentrations that are identical to or overlapping with the washing and elution concentrations recited in patented claim 1.
The optional limitations recited in pending claims 1 and 30 are also recited in patented claims 2, 3, and 7. Pending claims 8 and 37, 10, 12, 21 and 44, 22 and 45, 23 and 46, 25 and 48, 27 and 50, 29 and 52, respectively recite limitations that are overlapping with or identical to the limitations of patented claims 4, 5, 6, 8, 9, 10/11, 13, and 14/15.
Therefore, the patented and pending claims are related as species and genus, or they otherwise include overlapping subject matter.
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, 8, 10, 12, 14, 15, 21-23, 25, 27, 29, 30, 37, 39, 40, 44-46, 48, 50, and 52 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.
The terms “low” in claims 1 and 30, and “high” in claim 30, are relative terms which renders the claims indefinite. The terms “low” and “high” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Similarly, the vague expression “increasing concentration” in claim 1 does not inform the skilled artisan how to perform the method. The lack of clarity is not resolved in any dependent claim. Dependent claims 14 and 39 resolve the lack of clarity for the wash step but not for the elution step. Dependent claims 15 and 40 resolve the lack of clarity for the elution step but not the wash step.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 8, 10, 12, 14, 21, 27, 29, 30, 37, 39, 44, 50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Gagnon (US 2015/0353598, of record), in view of Beam et al. (US 2017/0159099, of record), Lin et al. (US 2016/0051695, of record) and US 20100280228 (Snyder).
Gagnon exemplifies monoclonal antibody capture on hydroxyapatite (HA) [0087]. Gagnon teaches washing the column with 5 mM sodium phosphate pH 6.7, which is a "low concentration of sodium phosphate buffer" as in pending claims 1, 14, 30, and 39. This was followed by elution with a 20 CV linear gradient to 300 mM phosphate pH 6.7, which is "gradually increasing concentration of said sodium phosphate buffer", as in pending claim 1, and a “high” concentration of phosphate buffer as in pending claim 30. Gagnon further teaches that a wash buffer removes unwanted contaminants and the intact antibody which is eluted from the column under conditions that leave aggregate antibody bound to the column [0074]. Gagnon teaches CHT Type II, as in pending claims 21 and 44, and 20 column volume wash, as in claim 12 [0087].
Gagnon.is directed to purification of monoclonal antibodies and does not specifically teach application of the disclosed method to antibody drug conjugates as in the pending claims.
Beam is directed to the making and use of antibody drug conjugates (whole document; [0045]). Beam teaches that many techniques are known for purification of antibody which includes chimeric, Fabs as well as those antibodies to be conjugated to a drug for therapeutic use. Beam teaches that such methods include ceramic hydroxyapatite with a phosphate gradient elution for separating antibodies from dimers, aggregates and leached Protein A among other contaminants [0161] [0075] [0077]. Thus, both Beam and Gagnon teach that antibody aggregates remain bound to the column during the elution step. In view of Beam, one of skill in the art would expect that the method of Gagnon would be effective for the purification of various forms of antibodies conjugated to drugs.
Lin also teaches purification of an anti-HER2-IgG1-Tap18Hr1 conjugate, which is considered an antibody drug conjugate, by applying a mixture with the conjugate to a hydroxyapatite column and washing with binding buffer, 10 mM sodium phosphate, pH 7.0 and eluting the ADC with 200 mM sodium phosphate, 10 mM NaCl, pH 7.0 [0284]. Thus, Lin exemplifies the “low concentration” washing buffer of pending claims 1 and 30, and the “high concentration” elution buffer of pending claim 30, as well as the pH limitations of claims 8 and 37. Furthermore, Lin also teaches that the ADC was diluted in binding buffer which included DMSO and then applied to the hydroxyapatite column [0284], as in pending claims 27 and 50.
Snyder teaches methods for purification of immunoconjugates. Snyder teaches
that ceramic hydroxyapatite types I and II are types of mixed mode support materials that are particularly useful for this purpose [0012][0014]. In some embodiments, the buffer is a phosphate buffer [0010], the washing and elution buffers may range from pH 5.5 to pH 8.5 [0007-0008]. Snyder teaches that it is advantageous to use low phosphate buffer concentrations (1-50 mM) during the loading phase [0065] and high phosphate buffer concentrations (at least 100 mM) for elution [0082].
Gagnon, Beam, Lin and Snyder are each directed to methods analogous to the methods of the pending claims. The initial presence of contaminants and removal of contaminants during the methods, as in claims 29 and 52, are implicit and intrinsic to all of the disclosed methods. Gagnon and Beam teach or suggest that the steps and conditions recited in the claims will separate aggregates from monomers and that they are applicable to all forms of antibodies. Lin demonstrates use of the general method with a known antibody-drug conjugate. A person of skill in the art would have a reasonable expectation that the suggested methods can, with routine optimization, be applied to a variety of antibody-drug conjugates. Snyder provides guidance for optimization. Therefore, the methods of claims 1, 8, 10, 12, 14, 21, 27, 29, 30, 37, 39, 44, 50, and 52 are prima facie obvious in view of Gagnon, Beam, Lin and Snyder.
Claims 23, 25, 46 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Gagnon, Beam, Lin and Snyder as applied to claims 1 and 30 above, and further in view of US 20140127211 (Geles) and US 20140363452 (Doroski)
As detailed above, Gagnon, Beam, Lin and Snyder teach or suggest the steps and general conditions of independent claims 1 and 30. Gagnon, Beam, Lin and Snyder do not teach that the ADC contains an average DAR of between 3 and 5 as in claims 23 and 46. Gagnon, Beam, Lin and Snyder do not teach an embodiment wherein the antibody is an anti-Notch 3 antibody conjugated to an aurostatin, as in claims 25 and 48.
Geles teaches various anti-Notch3 antibody-drug conjugates and also methods of using said anti-Notch3 antibodies and antibody-drug conjugates (ADCs) for the treatment of cancer [0003]. Geles teaches that the number of drug conjugated per antibody molecules, which is considered the "drug to antibody ratio" (DAR), ranges from an average of 1 to 12 such as about 1 to about 3 (p. 22, line 21). Geles further teaches an antibody drug conjugate having the formula recited in claims 25 and 48 [0219], as best as the instant disclosure can be discerned.
Doroski teaches anti-Notch ADCs with various payload combinations. Doroski teaches that anti-Notch ADCs with vc0101 linker payloads were more potent than other anti-Notch ADCs tested. [1373]. As is evidenced by the specification as filed at p. 18, the term "vc0101 linker payload" refers to the formula recited in claims 25 and 48.
Geles and Doroski provide teaching and motivation to make and use anti-Notch antibodies conjugated to an auristatin specifically have the structure recited in claims 25 and 48. It is noted that Beam teaches that the disclosed method for purifying antibody drug conjugates may be performed wherein the bound cytotoxic agent is an auristatin [0096] [0058]. One of skill in the art would expect to successfully apply Beam’s teaching together with guidance found in Gagnon, Lin and Snyder to purify the anti-Notch3 antibody-auristatin conjugates disclosed in Geles and Doroski, thereby performing the methods of pending claims 23, 25, 46 or 48. Therefore, the DAR and auristatin limitations of claims claims 23, 25, 46 or 48 are obvious embodiments of the general methods taught or suggested in Gagnon, Beam, Lin and Snyder.
Claims 22 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Gagnon, Beam, Lin, and Snyder as applied to claims 1 and 30 above, and further in view of US 20100234577 (Mazzola).
As detailed above, Gagnon, Beam, Lin and Snyder teach or suggest the steps and general conditions of independent claims 1 and 30. Beam, Lin and Snyder do not teach that the ADC preparation is first subjected to ion or anion exchange chromatography as recited in claims 22 and 45.
Gagnon, however, further teaches that embodiments of the invention may be practiced in combination with one or more other purification methods including anion and cation exchange chromatography [0030]. Thus, using different ion exchange methods in combination with hydroxyapatite chromatography was known in the art prior to the time the instant application was filed.
An example is found in Mazzola, which teaches purification of monoclonal antibodies from cell culture fluid using ion exchange prior to absorbing the IgG to hydroxyapatite and selectively eluting the product form impurities. (abstract). Thus, Mazzola teaches the same order of steps as in the instant claims. Therefore, claims 22 and 45 represent a combination of familiar elements according to known methods, which is obvious when it does no more than yield predictable results (see KSR Int'l V. Teleflex Inc., 127 S. Ct. 1727, 1739 (2007).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DANIEL C GAMETT, Ph.D., whose telephone number is (571)272-1853. The examiner can normally be reached on M-W 9:00 am-5:30pm, EST. Please note the examiner’s part-time schedule. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama can be reached on 5712722911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DANIEL C GAMETT/Primary Examiner
Art Unit 1647