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 .
DETAILED ACTION
Claims 1-28 are pending in the instant application.
Claims 10, 17-18, and 20-26 were previously withdrawn.
Rejections Withdrawn
The rejection to claim 28 under 35 USC §112(a) is withdrawn in view of claim amendment.
Species under review
Applicant previously elected without traverse the species:
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, wherein the elected species is present in instant claims 1-9, 11-16, 19, and 27-28.
The Examiner previously further included another species wherein i-ix is the same as above, except L4 is a linear C1-C20 alkylene group interrupted with O; and L5 is Valine-Citrulline, wherein the Examiner elected species is present in instant claims 1-9, 11-16, 19, and 27-28.
Rejections Maintained
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 (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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
Regarding the Applicant elected species
The rejection of claims 1-9, 11-16, 19, and 27-28 under 35 U.S.C. 103 as being unpatentable over WO 2017/137458 (VAN BERKEL SS et al. reference of record), White JB et al. (MAbs 2019 Apr;11(3):500-515, IDS reference), and van Geel R et al. (Bioconjugate Chem. 2015, 26, 11, 2233–2242, IDS reference) is maintained.
‘458 taught a method of conjugating an antibody to linker drug payload to produce an antibody drug payload conjugate of compound 56 with the structure:
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wherein
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(page 105),
wherein
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(Figure 3),
wherein the cAC10-(6-N3-GalNAc)2 is modified in the 6 position and undergoes conjugation to the bicyclononyne (BCN) (Example 34, pages 106-107 bridging paragraph). ‘458 taught an effective method of treating a subject with a CD30-expressing cancer wherein a pharmaceutical composition comprising an antibody drug payload conjugate that comprised an antibody targeted to CD30 and compound 56 and a pharmaceutically acceptable carrier was administered to the subject (page 108, Example 37a and Figure 8A).
‘458 did not teach a drug to antibody ratio of one, but this is obvious in view of White and van Geel.
White taught an antibody drug payload conjugate (ADC) with a drug to antibody ratio (DAR) of one, wherein the linker conjugate bound the antibody at two sites on an antibody, wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two (abstract). White taught an effective method of treating subjects with a HER2 expressing cancer wherein subjects were administered an HER2 targeting ADC with a DAR of 1 (Figure 7), wherein the linker drug was conjugated to the antibody at two sites, wherein the linker comprised a valine-alanine PABC linker (Fig. 1)
van Geel taught ADCs wherein the auristatin drugs MMAF and MMAE are conjugated to the ADC via a linker comprising PEG-glut-vc-PABC linker and led to greater than 95% conjugation (Table 1), wherein the structure of the linker is
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.
Regarding instant claims 1-9 and 11-13, it would have been obvious for a person having ordinary skill in the art to take the ADC of compound 56 of ‘458 with the structure:
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wherein
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, wherein
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, wherein the -N3-GalNAc is modified in the 6 position and connects to the bicyclononyne (BCN) – and:
1a) Exchange the ADC with a DAR of 2 for a DAR of 1 with two connection points as taught by White;
1b) Exchange one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the antibody and produce a DAR of 1 ADC with two connection points as taught by White;
2) include a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel; and
3) exchange the valine-citrulline cleavable moiety for a valine-alanine cleavable moiety.
This is obvious because the ADC of compound 56 of ‘458 was effective and:
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White.
a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and
ADCs that comprise a linker with a valine-alanine PABC linker prior to the drug are known to be effective.
There is a reasonable expectation of success because the ADC of compound 56 of ‘458 was effective and:
ADCs that bind the antibody at two sites are known to be effective and an ADC with a DAR of one are known to be effective and have improved biophysical properties and tolerability compared to ADCs with DAR of two.
a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and
ADCs that comprise a linker with a valine-alanine PABC linker prior to the drug are known to be effective.
This would produce an ADC with a DAR of one with a structure of:
with the structure:
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, wherein the -N3-GalNAc is modified in the 6 position and connects to the bicyclononyne (BCN), wherein the N3 and BCN can produce the connecting group Z via a 1,3-dipolar cycloaddition (instant claim 2), wherein Z is a triazole (instant claim 3), wherein the branching moiety is N (instant claim 8), wherein MMAE is an auristatin (instant claim 13). This meets the limitations of instant claims 1-9 and 11-13.
Regarding instant claims 27-28, it would have been obvious for a person having ordinary skill in the art to take the effective method of ‘458 of treating a subject with a CD30-expressing cancer by administering a pharmaceutical composition comprising an antibody drug conjugate that comprised an antibody targeted to CD30 and compound 56 and a pharmaceutically acceptable carrier to the subject – and: 1) exchange the ADC in the pharmaceutical composition of ‘458 for the ADC of ‘458, White, and van Geel above.
This is obvious because: 1) the ADC of ‘458, White, and van Geel above would target the CD30 expressing cancer with an ADC with a DAR of 1, wherein ADC with a DAR of 1 has been shown to have improved biophysical properties and tolerability compared to ADCs with DAR of two .
There is a reasonable expectation of success because: 1) the ADC of ‘458, White, and van Geel above would target the CD30 expressing cancer with an ADC with a DAR of 1, wherein ADC with a DAR of 1 has been shown to have improved biophysical properties and tolerability compared to ADCs with DAR of two.
Regarding instant claims 14-16 and 19, it would have been obvious for a person having ordinary skill in the art to take the method of ‘458 of producing an ADC by conjugating i) cAC10-(6-N3-GalNAc)2 modified in the 6 position, which is symmetrically functionalized with two reactive groups; to ii) a to a bicyclononyne (BCN) conjugated linker drug, and modify the method to produce the ADC with a DAR of one of ‘458, White, and van Geel by reacting the antibody comprising two symmetrical azide reactive groups to a drug linker wherein the R group of compound 56 of ‘458 is modified to:
1a) produce an ADC with a DAR of one by exchanging the ADC with a DAR of 2 for a DAR of 1 with two connection points as taught by White; 1b) exchange one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the antibody and produce a DAR of 1 ADC with two connection points as taught by White;
2) include a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel; and
3) exchange the valine-citrulline cleavable moiety for a valine-alanine cleavable moiety.
This is obvious because the method of ‘458 reacted the N3 azide functional group of cAC10-(6-N3-GalNAc)2 modified in the 6 position with the BCN-conjugated drug linker and a second BCN-conjugated drug linker connected to the branching moiety would allow connection to the antibody at the second location and produce a DAR of one and:
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White.
a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and
ADCs that comprise a linker with a valine-alanine PABC linker prior to the drug are known to be effective.
There is a reasonable expectation of success because the ADC of compound 56 underwent the same conjugation as taught by ‘458, but the two arms of the antibody linking moieties would produce an ADC with a DAR of one and:
ADCs that bind the antibody at two sites are known to be effective and an ADC with a DAR of one are known to be effective and have improved biophysical properties and tolerability compared to ADCs with DAR of two.
a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and
ADCs that comprise a linker with a valine-alanine PABC linker prior to the drug are known to be effective.
This method would produce an ADC with a DAR of one of ‘458, White, and van Geel above, wherein the N3 and the terminal BCN moieties (instant claim 16) can produce the connecting group Z via a 1,3-dipolar cycloaddition (instant claim 15), wherein the payload of MMAE is D (instant claim 19), and further meet the claim limitation of instant claims 14-16 and 19.
Response to Arguments
Applicant argues Van Berkel relates to methods for increasing the therapeutic index of a bioconjugate. See Van Berkel, at 4. To achieve this, Van Berkel uses a glycan-based conjugation strategy, which includes the use of two conjugation sites per antibody and the formation of homogeneous DAR 2 conjugates. Van Berkel does not teach or suggest any drawbacks to DAR 2 ADCs, nor does it suggest that the therapeutic index could be further improved by reducing payload number. To the contrary, Van Berkel demonstrates that controlled DAR 2 glycan conjugates can achieve an improved therapeutic index even with highly potent payloads, through site-specific attachment and optimized linker design. See id at 24. Accordingly, a person of ordinary skill in the art starting from VanBerkel would have found no motivation to change the conjugates from DAR2 ADCs to DAR I ADCs.
Applicant argues White uses a very different conjugation strategy compared to the conjugation strategy used to prepare the antibody-payload conjugate of the present claims and in Van Berkel. In particular, White utilizes a genetically engineered antibody containing a single disulfide bond in the hinge region, where the disulfide bond is reduced and subsequently reacted with the linkerdrug construct, thereby forming the DAR 1 ADC. See White, at 5-11, Abstract.
Applicant argues by contrast, the antibody-payload conjugates of the present claims conjugate the linker-drug construct through glycans. A person of ordinary skill in the art would have had no reasonable expectation of success in creating DAR 1 conjugates through glycan conjugation instead of a reduced disulfide bridge because glycans fundamentally differ from disulfide bonds in both chemical functionality and spatial organization on the antibody.
Applicant argues the cysteines forming the disulfide bridge are in close spatial proximity (approximately 2.05 A). The relative orientation and proximity of the cysteines are suitable for connection by a single linker. In contrast, antibody glycans are located on discrete sites on the antibody surface, typically on opposing heavy chains (and are thus widely separated in space), and do not possess any inherent spatial relationship that would suggest that two glycan moieties could be simultaneously connected by a single linker. Such a difference is depicted below:
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Applicant argues thus, unlike the reduced disulfide bridge taught by White, a person of ordinary skill in the art would not reasonably expect that two glycans have a spatial orientation and relationship that would allow for connection to a single linker-drug construct.
Applicant argues the teachings of van Geel further underscore this difference. As demonstrated in van Geel, glycan conjugation proceeds efficiently with bulky linker-drug constructs, and conjugation at one glycan site does not adversely interfere with conjugation at the second glycan site. See Van Geel, at 2236-37, Table 1. The high conjugation efficiency implies that the glycan sites are not sterically close to one another. If the glycan sites were in close spatial proximity, conjugation of a first bulky linker-drug construct would adversely affect the attachment of a second construct due to steric hindrance. The absence of such an effect in van Geel supports that the glycan sites are spatially separated and not predisposed to dual-point engagement by a single linker.
Additionally, Applicant notes that in the context of thiol conjugation at a former disulfide bridge, a person of ordinary skill in the art would expect that the linker-drug construct that results from the reaction with the first thiol would reduce the likelihood of a second linker-drug construct reacting with the second thiol due to steric hindrance and the close spatial proximity of the two thiol groups. White is able to achieve controlled two-point attachment because the thiols are pre-organized in a well-defined geometric relationship within a single disulfide bond.
Applicant argues due to the spatial organization of the glycans on the antibody, a person of ordinary skill in the art would have concerns regarding the connection of multiple glycan sites with a single linker. This could lead to inter-antibody crosslinking or polymerization, rather than the formation of DAR 1 ADCs, as shown below:
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Applicant argues accordingly, a person of ordinary skill in the art would have had no reasonable expectation that two glycan sites could be bridged by a single linker-drug construct in a controlled manner to yield a homogeneous DAR 1 ADC. Because these conjugation strategies operate through different reactive functional groups, different reaction mechanisms, and different structural assumptions about the antibody, a person of ordinary skill in the art would not have viewed glycan conjugation as a predictable or routine substitute for White's thiol-bridging strategy, contrary to the assertions in the Office Action.
Applicant argues in view of the foregoing, Applicant submits that the ability of the presently claimed methods to produce highly pure DAR 1 ADCs via glycan conjugation is surprising and unexpected, and the present claims are not obvious over the teachings of Van Berkel, White, and van Geel.
In response, Applicant's arguments filed 3/16/2026 have been fully considered but they are not persuasive. The obvious rational is above.
Regarding Van Berkel (‘458) and drawbacks to DAR 2 ADCs, the known effectiveness and improved properties of an ADC with a DAR of 1 was taught by White. As described above, White taught an antibody drug payload conjugate (ADC) with a drug to antibody ratio (DAR) of one, wherein the linker conjugate bound the antibody at two sites on an antibody, wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two (abstract). White taught an effective method of treating subjects with a HER2 expressing cancer wherein subjects were administered an HER2 targeting ADC with a DAR of 1 (Figure 7), wherein the linker drug was conjugated to the antibody at two sites, wherein the linker comprised a valine-alanine PABC linker (Fig. 1). Thus, the prior art had previously taught an ADC with a DAR of 1, wherein the linker conjugate bound the antibody at two sites on an antibody, was effective with desirable properties.
Regarding White uses a different conjugation strategy, White is described above and a DAR of one would be expected to be effective in other ADCs and have other desirable properties. Further, as described above, exchange of one of the
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White.
Regarding the reasonable expectation of success in creating DAR 1 conjugates through glycan conjugation instead of a reduced disulfide bridge, Van Berkel taught a method of conjugating an antibody to linker drug payload to produce an effective antibody drug payload conjugate of compound 56 with the structure:
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wherein
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(page 105),
wherein
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(Figure 3), wherein the cAC10-(6-N3-GalNAc)2 is modified in the 6 position and undergoes conjugation to the bicyclononyne (BCN) (Example 34, pages 106-107 bridging paragraph). Thus, the 2 represents conjugation at two separate glycans. There is a reasonable expectation of success of bridging the DAR 1 linker across opposing heavy chain constant regions of Van Berkel via the azide moieties to produce
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as shown above.
Regarding: 1) glycan spatial relationship and connection through a linker; 2) inter-antibody crosslinking or polymerization; and 3) van Geel implications of spatial separation, a person having ordinary skill in the art would not expect there to be orientation issues connecting glycans in this manner. Heavy chain constant region glycans are known to oppose each other and orient towards one another
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, wherein the opposing heavy chain glycans are known to orient close to one another (Krapp S et al. (J Mol Biol 2003 325(5):979-89.), Fig 2a). Thus, bridging the glycans that are oriented close to one another with a linker as described above would be expected to be successful and not produce inter-antibody crosslinking or polymerization, rather than the formation of DAR 1 ADCs.
Accordingly, a person of ordinary skill in the art would have had a reasonable expectation that two glycan sites could be bridged by a single linker-drug construct in a controlled manner to yield a homogeneous DAR 1 ADC as described above and be obvious over the teachings of Van Berkel, White, and van Geel.
Regarding the Examiner elected species
The rejection of claims 1-9, 11-16, 19, and 27-28 under 35 U.S.C. 103 as being unpatentable over WO 2017/137458 (VAN BERKEL SS et al. reference of record) and White JB et al. (MAbs 2019 Apr;11(3):500-515, IDS reference) is maintained.
‘458 taught a method of conjugating an antibody to linker drug payload to produce an antibody drug payload conjugate of compound 56 with the structure:
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wherein
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(page 105),
wherein
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(Figure 3),
wherein the cAC10-(6-N3-GalNAc)2 is modified in the 6 position and undergoes conjugation to the bicyclononyne (BCN) (Example 34, pages 106-107 bridging paragraph). ‘458 taught an effective method of treating a subject with a CD30-expressing cancer wherein a pharmaceutical composition comprising an antibody drug payload conjugate that comprised an antibody targeted to CD30 and compound 56 and a pharmaceutically acceptable carrier was administered to the subject (page 108, Example 37a and Figure 8A).
‘458 did not teach a drug to antibody ratio of one, but this is obvious in view of White.
White taught an antibody drug payload conjugate (ADC) with a drug to antibody ratio (DAR) of one, wherein the linker conjugate bound the antibody at two sites on an antibody, wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two (abstract). White taught an effective method of treating subjects with a HER2 expressing cancer wherein subjects were administered an HER2 targeting ADC with a DAR of 1 (Figure 7), wherein the linker drug was conjugated to the antibody at two sites, wherein the linker comprised a valine-alanine PABC linker (Fig. 1)
Regarding instant claims 1-9 and 11-13, it would have been obvious for a person having ordinary skill in the art to take the ADC of compound 56 of ‘458 with the structure:
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wherein
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, wherein
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, wherein the -N3-GalNAc is modified in the 6 position and connects to the bicyclononyne (BCN) – and:
1a) Exchange the ADC with a DAR of 2 for a DAR of 1 with two connection points as taught by White; and
1b) Exchange one of the
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to bind the antibody and produce a DAR of 1 ADC with two connection points as taught by White.
This is obvious because the ADC of compound 56 of ‘458 was effective and:
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White.
There is a reasonable expectation of success because the ADC of compound 56 of ‘458 was effective and:
ADCs that bind the antibody at two sites are known to be effective and an ADC with a DAR of one are known to be effective and have improved biophysical properties and tolerability compared to ADCs with DAR of two.
This would produce an ADC with a DAR of one with a structure of:
with the structure:
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, wherein the -N3-GalNAc is modified in the 6 position and connects to the bicyclononyne (BCN), wherein the N3 and BCN can produce the connecting group Z via a 1,3-dipolar cycloaddition (instant claim 2), wherein Z is a triazole (instant claim 3), wherein the branching moiety is N (instant claim 8), wherein MMAE is an auristatin (instant claim 13). This meets the limitations of instant claims 1-9 and 11-13.
Regarding instant claims 27-28, it would have been obvious for a person having ordinary skill in the art to take the effective method of ‘458 of treating a subject with a CD30-expressing cancer by administering a pharmaceutical composition comprising an antibody drug conjugate that comprised an antibody targeted to CD30 and compound 56 and a pharmaceutically acceptable carrier to the subject – and: 1) exchange the ADC in the pharmaceutical composition of ‘458 for the ADC of ‘458 and White.
This is obvious because: 1) the ADC of ‘458 and White above would target the CD30 expressing cancer with an ADC with a DAR of 1, wherein ADC with a DAR of 1 has been shown to have improved biophysical properties and tolerability compared to ADCs with DAR of two.
There is a reasonable expectation of success because: 1) the ADC of ‘458 and White above would target the CD30 expressing cancer with an ADC with a DAR of 1, wherein ADC with a DAR of 1 has been shown to have improved biophysical properties and tolerability compared to ADCs with DAR of two.
Regarding instant claims 14-16 and 19, it would have been obvious for a person having ordinary skill in the art to take the method of ‘458 of producing an ADC by conjugating i) cAC10-(6-N3-GalNAc)2 modified in the 6 position, which is symmetrically functionalized with two reactive groups; to ii) a to a bicyclononyne (BCN) conjugated linker drug, and modify the method to produce the ADC with a DAR of one of ‘458 and White by reacting the antibody comprising two symmetrical azide reactive groups to a drug linker wherein the R group of compound 56 of ‘458 is modified to:
1a) produce an ADC with a DAR of one by exchanging the ADC with a DAR of 2 for a DAR of 1 with two connection points as taught by White; and 1b) exchange one of the
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to bind the antibody and produce a DAR of 1 ADC with two connection points as taught by White.
This is obvious because the method of ‘458 reacted the N3 azide functional group of cAC10-(6-N3-GalNAc)2 modified in the 6 position with the BCN-conjugated drug linker and a second BCN-conjugated drug linker connected to the branching moiety would allow connection to the antibody at the second location and produce a DAR of one and:
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White.
There is a reasonable expectation of success because the ADC of compound 56 underwent the same conjugation as taught by ‘458, but the two arms of the antibody linking moieties would produce an ADC with a DAR of one and:
ADCs that bind the antibody at two sites are known to be effective and an ADC with a DAR of one are known to be effective and have improved biophysical properties and tolerability compared to ADCs with DAR of two.
This method would produce an ADC with a DAR of one of ‘458 and White above, wherein the N3 and the terminal BCN moieties (instant claim 16) can produce the connecting group Z via a 1,3-dipolar cycloaddition (instant claim 15), wherein the payload of MMAE is D (instant claim 19), and further meet the claim limitation of instant claims 14-16 and 19.
Response to Arguments
The arguments against Van Berkel and White are discussed above.
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.
Regarding the Examiner and the Applicant elected species
The provisionally rejected claims 1-9, 11-16, 19, and 27-28 on the ground of nonstatutory double patenting as being unpatentable over claims 1-26 of copending Application No. 17/812,155 in view of WO 2017/137458 (VAN BERKEL SS et al. reference of record), White JB et al. (MAbs 2019 Apr;11(3):500-515, IDS reference), and van Geel R et al. (Bioconjugate Chem. 2015, 26, 11, 2233–2242, IDS reference) is maintained.
Copending claims 1-14 and 25 of ‘155 taught an antibody payload conjugate having the structure (1).
Copending claims 15-19 of ‘155 taught a method of preparing an antibody payload conjugate having the structure (1) with a DAR of 1.
Copending claim 26 taught a method of treating cancer in a subject comprising administering to the subject a composition of a pharmaceutical composition of an antibody payload conjugate having the structure (1) and a pharmaceutically acceptable carrier.
‘155 taught an antibody payload conjugate having the structure (1):
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In copending claim 1,
wherein Z can be obtained by a 1,3-dipolar cycloaddition in copending claim 2,
wherein Z contains a triazole in copending claim 3,
wherein each of Li, L2 and L3, if present, are a chain of at least 2 atoms selected from C, N, O, S and P in copending claim 4,
wherein the structure is structure (5)
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in copending claim 5,
wherein L1 and L2 are the same in copending claim 7,
wherein L1 and L2 are the same, each occurrence of Su is the same, each occurrence of Z is the same, each occurrence of G is the same, and each occurrence of e is the same in copending claim 8,
wherein branching moiety BM is N in copending claim 9,
wherein L3 is -(L4)n-(L5)o-(L6)pLL7)q-, wherein L4, L5, L6 and L7 are linkers that together form linker L3; n, o, p and q are individually 0 or 1 in copending claim 10,
wherein L5 is represented by general structure (27)
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wherein R17 = CH3 or CH2CH2CH2NHC(O)NH2 in copending claim 12,
wherein L6 is a para-aminobenzyloxycarbonyl (PABC) derivative according to structure (25)
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wherein R3 is H in copending claim 13,
wherein D is auristatin copending claim 14, and
wherein the antibody- payload conjugate according to claim 1 is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier in copending claim 25.
Regarding instant claims 14-16 and 19, ‘155 taught a method of preparing an antibody payload conjugate having the structure (1) comprising the steps of:
reacting a compound having structure (2) containing at least two reactive groups Q with an antibody having structure (3), which is symmetrically functionalized with two reactive groups F:
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in copending claim 15,
wherein the cycloaddition is a 1,3-dipolar cycloaddition in copending claim 16,
wherein Q comprises a terminal cyclooctyne as BCN in copending claim 17,
wherein in step (a) a functionalized antibody according to structure (1) is obtained wherein D is the payload, and step (b) is not performed in copending claim 18,
The claims of ‘155 did not teach a single embodiment with the exact structure of the Applicant or Examiner elected species, but this is obvious in view of ‘468, White, and van Geel.
‘458 taught a method of conjugating an antibody to linker drug payload to produce an antibody drug payload conjugate of compound 56 with the structure:
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wherein
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(page 105),
wherein
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(Figure 3),
wherein the cAC10-(6-N3-GalNAc)2 is modified in the 6 position and undergoes conjugation to the bicyclononyne (BCN) (Example 34, pages 106-107 bridging paragraph). ‘458 taught an effective method of treating a subject with a CD30-expressing cancer wherein a pharmaceutical composition comprising an antibody drug payload conjugate that comprised an antibody targeted to CD30 and compound 56 and a pharmaceutically acceptable carrier was administered to the subject (page 108, Example 37a and Figure 8A).
White taught an antibody drug payload conjugate (ADC) with a drug to antibody ratio (DAR) of one, wherein the linker conjugate bound the antibody at two sites on an antibody, wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two (abstract). White taught an effective method of treating subjects with a HER2 expressing cancer wherein subjects were administered an HER2 targeting ADC with a DAR of 1 (Figure 7), wherein the linker drug was conjugated to the antibody at two sites, wherein the linker comprised a valine-alanine PABC linker (Fig. 1)
van Geel taught ADCs wherein the auristatin drugs MMAF and MMAE are conjugated to the ADC via a linker comprising PEG-glut-vc-PABC linker and led to greater than 95% conjugation (Table 1), wherein the structure of the linker is
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.
Regarding instant claims 1-9 and 11-13, it would have been obvious to take the antibody payload conjugate of copending claims 1-10, 12-14 of an antibody payload conjugate of structure (5) comprising
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wherein Z can be obtained by a 1,3-dipolar cycloaddition in copending claim 2,
wherein Z contains a triazole in copending claim 3,
wherein each of Li, L2 and L3 are a chain of at least 2 atoms selected from C, N, O, S and P in copending claim 4,
wherein L1 and L2 are the same in copending claim 7,
wherein L1 and L2 are the same, each occurrence of Su is the same, each occurrence of Z is the same, each occurrence of G is the same, and each occurrence of e is the same in copending claim 8,
wherein branching moiety BM is N in copending claim 9,
wherein L3 is -(L4)n-(L5)o-(L6)pLL7)q-, wherein L4, L5, L6 and L7 are linkers that together form linker L3; n, o, p and q are individually 0 or 1 in copending claim 10,
wherein L5 is represented by general structure (27)
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wherein R17 = CH3 or CH2CH2CH2NHC(O)NH2 in copending claim 12,
wherein L6 is a para-aminobenzyloxycarbonyl (PABC) derivative according to structure (25)
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wherein R3 is H in copending claim 13,
wherein D is auristatin copending claim 14, and
wherein the antibody- payload conjugate according to claim 1 is in a pharmaceutical composition further comprising a pharmaceutically acceptable carrier in copending claim 25 – and:
include -N3-GalNAc modified in the 6 position as an attachment to the antibody and connects to the bicyclononyne (BCN) as taught by ‘458;
include the linker
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as L1 and L2 as taught by ‘458 of compound 56 for attachment to the N branching moiety;
include either: i) a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel; or ii) a
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as taught by ‘458; and
either: i) exchange the valine-citrulline cleavable moiety for a valine-alanine cleavable moiety of White; or ii) do not change the valine-citrulline cleavable moiety as taught in ‘458.
This is obvious because:
the ADC of compound 56 of ‘458 was effective and included the -N3-GalNAc modified in the 6 position as an attachment to the antibody and connects to the bicyclononyne (BCN) linker;
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White. Additionally, copending claim 7 taught L1 and L2 were the same;
i) a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and ii) the drug linker
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was taught by ‘458; and
ADCs that comprise a linker with a: i) valine-alanine PABC linker; or ii) valine-citrulline PABC linker, prior to the drug are known to be effective.
There is a reasonable expectation of success because:
the ADC of compound 56 of ‘458 was effective and included the -N3-GalNAc modified in the 6 position as an attachment to the antibody and connects to the bicyclononyne (BCN) linker;
White taught an ADC with a DAR of one, wherein the linker conjugate bound the antibody at two sites on an antibody, and wherein the ADC with a DAR of one was effective and had improved biophysical properties and tolerability compared to ADCs with DAR of two. Further, exchange of one of the
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drug linkers of compound 56 after the N branching moiety for
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to bind the bicyclononyne (BCN) N3-GalNAc modified in the 6 position moiety would produce an ADC with a DAR of one with two connection points as taught by White. Additionally, copending claim 7 taught L1 and L2 were the same, so L1 and L2 as the same was expected to be reasonable;
i) a glutaryl moiety between the PEG moiety and the cleavable amino acid PABC linker moiety as taught by van Geel and had greater than 95% conjugation; and ii) the drug linker
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was taught by ‘458 as effective; and
ADCs that comprise a linker with a: i) valine-alanine PABC linker; or ii) valine-citrulline PABC linker, prior to the drug are known to be effective.
This meets the limitations of instant claims 1-9 and 11-13 for both the Applicant and Examiner elected species.
Regarding instant claims 27-28, it would have been obvious for a person having ordinary skill in the art to take the method of copending claim 26 of a method of treating cancer in a subject comprising administering to the subject a composition of a pharmaceutical composition of an antibody payload conjugate having the structure (1) and a pharmaceutically acceptable carrier – and: 1) exchange the ADC in the pharmaceutical composition of ‘155 for the ADC of ‘155, ‘458, White, and van Geel above.
This is obvious because: 1) the ADC of ‘155, ‘458, White, and van Geel above exchanges one ADC payload molecule for another.
There is a reasonable expectation of success because: 1) the ADC of ‘155, ‘458, White, and van Geel above would exchange one ADC payload molecule for another that performs the same function of delivering a drug payload to cancer cells.
Regarding instant claims 14-16 and 19, it would have been obvious for a person having ordinary skill in the art to take the methods of copending claims 15-18 of a method of preparing an antibody payload conjugate having the structure (1) comprising the steps of:
reacting a compound having structure (2) containing at least two reactive groups Q with an antibody having structure (3), which is symmetrically functionalized with two reactive groups F:
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in copending claim 15, wherein the cycloaddition is a 1,3-dipolar cycloaddition in copending claim 16, wherein Q comprises a terminal cyclooctyne as BCN in copending claim 17, wherein in step (a) a functionalized antibody according to structure (1) is obtained wherein D is the payload, and step (b) is not performed in copending claim 18 – and:
producing an ADC by conjugating i) cAC10-(6-N3-GalNAc)2 modified in the 6 position, which is symmetrically functionalized with two reactive groups; to ii) a bicyclononyne (BCN) conjugated linker drug, and modify the method to produce the ADC with a DAR of one of ‘155, ‘458, White, and van Geel above by reacting the antibody comprising two symmetrical azide reactive groups to a drug linker wherein the R group comprises the two armed linker from the BCN to the auristatin payload above.
This is obvious because the method of ‘458 reacted the N3 azide functional group of cAC10-(6-N3-GalNAc)2 modified in the 6 position with the BCN-conjugated drug linker and a second BCN-conjugated drug linker connected to the branching moiety would allow connection to the antibody at the second location and produce a DAR of one and:
There is a reasonable expectation of success because: 1) the ADC of compound 56 underwent the same conjugation as taught by ‘458, but the two arms of the antibody linking moieties would produce an ADC with a DAR of one.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
The arguments against Van Berkel and White are discussed above.
Applicant requests that the double patenting rejection over co-pending application 17/812,155 be held in abeyance (Remarks p. 14). A request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see 37 CFR 1.111(b) and MPEP §714.02). Thus, the double patenting rejections of record have been maintained as no response to these rejections has been filled by applicant at this time.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN J SKOKO III whose telephone number is (571)272-1107. The examiner can normally be reached M-F 8:30 - 5:00.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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