DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Request for Continued Examination (RCE)
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3/12/26 has been entered.
Priority
This application is a CON of 15/517,969 (04/10/2017 ABN); 15/517,969 is a 371 of PCT/GB2015/052953 (10/08/2015); and claims foreign priority to: UNITED KINGDOM 1418986.4 (10/24/2014), UNITED KINGDOM 1418984.9 (10/24/2014), UNITED KINGDOM 1418989.8 (10/24/2014).
Status
Claims 1, 2, 5-7, 11, 13-39 are currently pending.
Rejections not reiterated in this action are withdrawn.
Election/Restrictions
Applicant elected with traverse Group I, claims 1-23, in the reply of 7/14/2021. The elected species of ADC 10 is the conjugate of brentuximab with the following reagent 9
bis-mPEG(7u)sulfone-propanoyl-benzamide-L-Glu-[val-cit-PAB-MMAE]-[PEG(24u)-OMe]:
(conjugated to Brentuximab), corresponding to Formula (I):
PNG
media_image1.png
94
237
media_image1.png
Greyscale
where W’ is –C(O)- ; A and B are –CH2- ; Nu and Pr are as depicted below:
PNG
media_image2.png
206
199
media_image2.png
Greyscale
and a “linker” “includes a portion”:
PNG
media_image3.png
72
205
media_image3.png
Greyscale
corresponding to the portion -Val-Cit-NH-phenyl-CH2-OC(O)-; where the therapeutic is Monomethyl auristatin E (MMAE):
PNG
media_image4.png
79
405
media_image4.png
Greyscale
.
As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. Therefore, the provisional election of species is given effect, the examination is restricted to the elected species only, and claims not reading on the elected species are held withdrawn. MPEP 803.02; Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (Bd. Pat. App. lnt. 1987).
Should applicant, in response to this rejection of the Markush-type claim, overcome the rejection through amendment, the amended Markush-type claim will be reexamined to the extent necessary to determine patentability of the Markush-type claim. See MPEP 803.02.
Claim Rejections - 35 USC § 103 over Lyon, Khalili, and Balan
Claims 1, 2, 5, 7, 11, 26-28, 31, 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Lyon et al. (WO2015057699) in view of Khalili et al. (Bioconjugate Chem. 2012, 23, p. 2262−2277), Balan et al. (Bioconjugate Chem. 2007, 18, p. 61-76).
Regarding claim 1, Lyon claims antibody drug conjugates of the formula (claims 1-2):
PNG
media_image5.png
176
243
media_image5.png
Greyscale
which reads on the elected species (ADC 10 is the conjugate of brentuximab with the following reagent 9 bis-mPEG(7u)sulfone-propanoyl-benzamide-L-Glu-[val-cit-PAB-MMAE]-[PEG(24u)-OMe]) as follows: L=brentuximab - Lyon teaches L is preferably an antibody ([0205]) including brentuximab ([0218]); Z=bis-sulfone-propanoyl-benzamide - Lyon teaches Z is a group that has a reactive site that can form a bond with a sulfhydryl group of L ([0265]-[0270]), such as maleimide ([0270]-[0273]); Lp=glutamic acid LP is a “parallel connector” (claim 1) which includes an amino acid with a preferred glutamic acid also used as a illustrative example ([0132], [0142], [0147], [0155], [0163]); PEG=PEG(24u)-OMe - Lyon’s Example 6/compound 24 below; As is absent (m=1) (Example 6/compound 24 below); X-D=val-cit-PAB-MMAE - Lyon’s Example 6 below ([0230]-[0232]), m=1, p=4 (Example 6/compound 24 below). Thus, Lyon’s claim 1 encompasses instant claim 1 and the elected species.
Lyon’s Example 6 shown below (compound 24: MDpr-Lys(PEG24)-ValCit-PAB-MMAE, p. 206-208; circled to show difference from instant claims/elected species):
PNG
media_image6.png
644
1646
media_image6.png
Greyscale
differs from the elected species by the circled group above – a maleimide group vs. a bis-sulfone group.
Although Lyon teaches Z is a group with a reactive site that can form a bond with a sulfhydryl group of L ([0265]-[0270]), such as maleimide ([0270]-[0273]; claim 16), Lyon does not specifically teach Z is bis-sulfone-propanoyl-benzamide as in the elected species.
Khalili teaches the conjugation to an antibody utilizing a bis-sulfone reagent that attaches to two cysteines of the antibody. Khalili teaches that bis-sulfone conjugates are superior because they do not suffer the problems of maleimide conjugates that are labile to hydrolysis and exchange reactions (p. 2263). Khalili teaches the mechanism of attachment in scheme 1 and 2 (p. 2263):
PNG
media_image7.png
208
1504
media_image7.png
Greyscale
PNG
media_image8.png
703
1502
media_image8.png
Greyscale
Similarly, Balan teaches a bis-sulfone reagent for conjugation to biomolecules including antibodies. Balan’s reagent 3:
PNG
media_image9.png
207
569
media_image9.png
Greyscale
conjugates to two cysteine residues on the antibody (p. 65). Balan teaches that an antibody can be site-specific across a native disulfide bond using three-carbon bridges without destroying their tertiary structure or abolishing their biological activity (abstract, p. 69). Balan teaches that the reagents such as maleimide are inferior to the bisulfone because “these reagents are unable to rebridge reduced disulfides in the way that our PEG monosulfone 4 can bridge the reduced disulfide bond” (p. 65). Therefore the bis-sulfone-propanoyl-benzamide taught by Khalili and Balan and within the scope of Lyon’s Z group are equivalents known for the same purpose and would have been prima facie obvious (MPEP 2144.06).
One of ordinary skill in the art following the teaching of Lyon would have reasonably considered modifying Example 6’s maleimide with an alternate “Z” groups known in the art and within Lyon’s scope for attaching the conjugate to an antibody including the bis-sulfone-propanoyl-benzamide taught by Khalili and Balan because they were art-recognized equivalents for the same purpose – i.e. a reactive group for forming a sulfhydryl bond with an antibody. Furthermore, one of ordinary skill in the art would have considered the modification because Khalili and Balan teach that bis-sulfone is superior to maleimide in the context of forming antibody conjugates.
All of the references relate to conjugating functional elements to improve the utility and stability of the therapeutic agents, thus one of ordinary skill in the art would have reasonably considered their combination. One of ordinary skill in the art would have compared the success of Lyon, Khalili, and Balan and recognize that the improvements would be combinable because of the similarities in the mode of operation and structure of the conjugating agents. Specifically, Lyon teaches that the Z group needs to be capable of reacting to attach to the antibody, while Khalili and Balan teaches such an improved group. One of ordinary skill in the art would have a reasonable expectation of success in utilizing the bis-sulfone group in place of the maleimide group because they are within Lyon’s Z group, share the function of attachment, and Khalili and Balan teach that bis-sulfone possesses superior properties.
Thus, one of ordinary skill in the art would have considered improving Lyon’s “Z” group with a bis-sulfone-propanoyl-benzamide to improve therapeutic utility and arrive at the claimed invention with a reasonable expecation of success.
Regarding claim 2 specifying R of the terminal PEG -CH2CH2OR group, Lyon teaches R is CH3.
Regarding claim 5, modified Lyon teaches that the Z group conjugates to sulfur atom in the antibody.
Regarding claim 7, modified Lyon teaches the therapeutic agent MMAE.
Regarding claim 11, modified Lyon teaches the bis-sulfone-propanoyl-benzamide as in Balan and Khalili.
Regarding claim 26, Lyon teaches Example 6 (compound 24: MDpr-Lys(PEG24)-ValCit-PAB-MMAE, p. 206-208) with the same PAB structure.
Regarding claim 27, Lyon teaches Example 6 (compound 24: MDpr-Lys(PEG24)-ValCit-PAB-MMAE, p. 206-208) with the same Val-Cit structure.
Regarding claim 28, modified Lyon teaches the same structure as reagent 1.
Regarding claim 31, modified Lyon teaches the same structure as reagent 1 and Lyon teaches conjugation preferably with an antibody ([0205]) including brentuximab ([0218]).
Regarding claim 35, Lyon teaches PEG(24u)-OMe in Example 6/compound 24.
Regarding claim 36, modified Lyon teaches the same structure as reagent 1 and Lyon teaches conjugation preferably with an antibody ([0205]) including brentuximab ([0218]) which when conjugated forms the structure of the first alternative in the claim.
Regarding claim 37-38, modified Lyon teaches the same structure as reagent 1 and Lyon teaches conjugation preferably with an antibody ([0205]) including brentuximab ([0218]) which when conjugated forms the structure of the claim.
Response to Remarks - 35 USC § 103 over Lyon, Khalili, and Balan
Applicant argues that the cited references are incompatible and one of ordinary skill in the art would have not been motivated to combine them because of the different sizes of PEG and the purpose of using PEG.
This argument is not persuasive because each of the references are in the same field of endeavor of pharmaceutical conjugates. With regard to use of PEG, Lyon teaches that there is a desired effect (i.e., decrease in clearance and consequent in increase in exposure) that competes with (or must be balanced against) an undesired effect (i.e., increasing the number PEG subunits may result in a decreased diffusivity and diminish the ability of the Ligand-Drug Conjugate to penetrate into a tumor)(Lyon [0246]). Lyon teaches that because of these two competing pharmacokinetic effects, it is desirable to use a PEG that is sufficiently large to decrease the lipid drug conjugate (LDC) clearance thus increasing plasma exposure, but not so large as to greatly diminish its diffusivity, which may reduce the ability of the Ligand-Drug Conjugate to reach the intended target cell population (Lyon [0246]). Furthermore, Lyon specifically teaches examples where PEG is 24-mer (compound 24).
Applicant argues that one of ordinary skill in the art would not have viewed maleimide and bis-sulfone as art-recognized equivalents for the same purpose because it would affect DAR (drug-to-antibody-ratio).
This argument is not persuasive because each of Khalili and Balan compare the two groups by their means of attachment and resulting benefits and specifically describes how the two differ and thus bis-sulfones are beneficial with regard to bonding and hydrolysis (Kahlili p. 2263; Balan p. 65).
Applicant argues that there are unexpected and synergistic result from the “combination of a pendant PEG chain and a bis-sulfone attachment group”.
Applicant’s argument and the declaration of Nicolas Camper providing details experiments conducted that show a combination of a pendant PEG chain and a bis-sulfone attachment group provides unexpected and synergistic effects were fully considered and not found persuasive. First, the claims are not commensurate in scope with any alleged unexpected result - claim 1 does not requires a bis-sulfone group and contains 2-50 PEG units, while the argument and experiments relate to results of bis-sulfone vs. maleimide and PEG 24u vs. 1u, i.e. DM004, DM006, DM0011, DM0012. Second, Lyon teaches the optimization of PEG scaffold to improve the physical properties of the conjugate and improve stability ([0366]-[0368]), including Lyon’s Example 6 has a pendant PEG chain, which one of ordinary skill in the art would know would affect stability and efficacy – thus an expected result.
Applicant also argues that Exhibit E of the declaration establishes an unexpected result efficacy at lower dose evidenced by ADC-1 vs. -2 at 0.5 mg/kg.
A review of the data shows substantial differences in ADC-1 and -2 including the gluconaride, number of PEG chains, and number of drug payloads, MMAE (2 vs. 1). Thus, the comparison is not to the closest prior art compound and in addition is not commensurate in scope with the claimed invention because of the single vs. dual MMAE elements. Furthermore, one of ordinary skill in the art would have expected a therapeutic having twice the number of drugs to be more effective at a lower dose.
Applicant has failed meet their burden of establishing how the results described in the declarations are indeed unexpected and of practical and statistical significance. See MPEP 716.02(b). MPEP § 716.02(c) requires the examiner to weigh the evidence of secondary considerations against that supporting obviousness. “Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978).” In this case, Applicant’s argument and the Evans declaration has not outweighed the strong evidence favoring obviousness by a “preponderance of the evidence” (see MPEP 706 I).
Claim Rejection - 35 USC § 103 over Lyon, Khalili, Balan, and Doronina
Claims 34 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Lyon et al. (WO 2015/057699) in view of Khalili et al. (Bioconjugate Chem. 2012, 23, p. 2262−2277), and Balan et al. (Bioconjugate Chem. 2007, 18, p. 61-76) as applied to claims 1, 2, 5, 7, 11, 26-28, 31, 35-38 above and further in view of Doronina et al. (US7994135).
Regarding new claim 34 and 39 specifying DAR is 4, Lyon teaches “p is an integer ranging from 1 to 14, preferably 2 to 12” and includes in vivo examples where p is 4 and 8 (i.e. p=4: Fig. 16 “cAC10-10, 0.3 mg/kg”, p. 231: “providing cures in 5/6 mice”). Although Lyon focuses on examples where p is 8, one of ordinary skill in the art would have known that such a value requires optimization in view of the success of Doronina. Doronina claims structurally related ADCs (claim 1), for example trastuzumab-MC-vc-PAB-MMAF:
PNG
media_image10.png
158
853
media_image10.png
Greyscale
, and reports in vivo results in Table 2d and col. 135 (emphasis added):
In a surprising and unexpected discovery, the in vivo anti-tumor activity results of the ADC in Table 2d show generally that ADC with a low average number of drug moieties per antibody showed efficacy, e.g., tumor doubling time>15 days and mean log cell kill>1.0. FIG. 16 shows that for the antibody drug conjugate, trastuzumab-MC-vc-PAB-MMAF, the mean tumor volume diminished and did not progress where the MMAF:trastuzumab ratio was 2 and 4, whereas tumor progressed at a ratio of 5.9 and 6, but at a rate lower than Vehicle (buffer). The rate of tumor progression in this mouse xenograft model was about the same, i.e. 3 days, for Vehicle and trastuzumab. The results suggest that at least for trastuzumab ADC, the optimal ratio of drug moieties per antibody may be less than about 8, and may be about 2 to about 4.
Thus, one of ordinary skill in the art would have considered optimizing within Lyon’s claimed range of p including to a value of 4 based on the success of Doronina.
One of ordinary skill in the art would be well versed in the techniques of altering reactive groups to improve antibody drug conjugates (ADCs) to optimize the drug to antibody ratio (DAR) (i.e. Lyon p. 2-3). One of ordinary skill in the art would consider routine and well within their technical grasp the process of optimizing ADCs to improve therapeutic utility through interchanging a reactive group such as Lyon’s “Z” maleimide with a functional equivalent.
Doronina claims structurally related ADCs (claim 1), for example trastuzumab-MC-vc-PAB-MMAF which one of ordinary skill in the art would have considered because they are both ADCs and was readily combinable with the teaching of Lyon with PEGylation. Further, Doronina discusses the optimal DAR (col. 135: “for trastuzumab ADC, the optimal ratio of drug moieties per antibody may be less than about 8, and may be about 2 to about 4.”), which one of ordinary skill in the art would have considered highly relevant to the teaching of Lyon.
Response to Remarks - 35 USC § 103 over Lyon, Khalili, Balan, and Doronina
Applicant argues that one of ordinary skill in the art would not necessarily arrive at a DAR of 4 because although brentuximab may have four interchain disulfide bonds, DAR is not solely determined by the number of conjugation sites and the only information about DAR provided by Lyon is DAR of at least 6.
Lyon’s Example 17 (“ADCs loaded at 4-drugs per antibody with PEG24”) unambiguously teaches at [0540] that at “1 mg/kg, both PEGylated (cAC10-10) and non-PEGylated (cAC10-1) were equipotent, providing cures in 5/6 mice” and both
PNG
media_image11.png
200
400
media_image11.png
Greyscale
and
PNG
media_image12.png
200
400
media_image12.png
Greyscale
in Figure 16 are equipotent. Lyon’s discussion as to why the PEGylated form at a lower dose was less effective because of the size of the PEG ([0541]: “This may be due to impaired enzymatic drug release or decreased permeability due the increase in conjugate size upon PEGylation.”) but does not suggests DAR=4 would be ineffective. Lyon further describes experiments confirming that the PEG size is a relevant consideration in efficacy in Example 18 ([0545]). Although Lyon demonstrates varied success in the examples with different “drug loading” (DAR), one of ordinary skill in the art would have understood that the DAR would be optimized using routine experiments as was performed by Lyon among Lyon’s specific teaching of DAR values ranging “from 1 to 14, preferably 2-12” ([0422]). Lyon states the need addressed is to allow for higher drug loading while maintaining favorable PK properties ([0010]) which one of ordinary skill in the art would have known was a balance as described by Lyon ([0008]-[0009]). As per MPEP 2145, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). In this case, Lyon does not criticize, discredit, or otherwise discourage the use of p=4 (DAR=4), and in fact states that 4 is within the preferable range. While Lyon may teach success in demonstrations with DAR=8 this does not discourage DAR=4 within the stated preferable range. Thus, Lyon does provide significant motivation regarding DAR of 4 such that one of ordinary skill in the art would arrive at the claimed invention with a reasonable expectation of success. Thus, the argument is not persuasive.
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, 2, 5, 7, 11, 26-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-21 of U.S. Patent No. US10835616. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent teaches Example 24 with brentuximab conjugates with reagent 25 is the same as the instant elected species reagent
PNG
media_image13.png
579
1858
media_image13.png
Greyscale
One of ordinary skill in the art construing the patent claims 1-21, including the utility of the claimed conjugating agent, would have considered Example 24 and arrived at the claimed invention.
Claim Objections
Claim 37 is objected to for not ending with a period.
Conclusion
The claims are not in condition for allowance.
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 extension fee 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 ROBERT H HAVLIN whose telephone number is (571)272-9066. The examiner can normally be reached on 9am - 6pm.
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, Kortney Klinkel can be reached on (571) 270-5293. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ROBERT H HAVLIN/ Primary Patent Examiner, Art Unit 1626
Prosecution Insights