`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PHIGENIX
`PHIGENIX
`EXHIBIT 1037
`EXHIBIT 1037
`
`
`
`i 1
`
`EI I 3
`
`i
`
`PATENT APPLICATION
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`In re appiication of
`
`Rita STEEVES, et a1.
`
`
`Docket No: EAESEGQ
`
`Appln. No.: 10/960,602
`
`Group Art Unit: 1642
`
`Confirmation No.: 8576
`
`Examiner: Brandon J. FETI‘EROLF
`
`Filed: October 8, 2004
`
`For: METHOD OF TARGETING SPECIFIC CELL POPULATIONS USING CELL»BINDING
`AGENT MAYTANSINOID CONJUGATES LINKED VIA A NON-CLEAVABLE
`
`LINKER, SAID CONJUGATES AND METHODS OF MAKING SAID CONJUGATES
`
`FIRST DECLARATION UNDER 37 C.F.R. § 1.132
`
`Mail Stop Amendment
`Commissioner for Patents
`PO. Box 1450
`
`Alexandria, VA 22313-1450
`
`Sir:
`
`I, Ravi Chari, hereby declare and state:
`
`THAT I am a citizen of the United States;
`
`THAT I have received the degree of PhD. in chemistry from the University of Detroit,
`
`Detroit, MI, in 1979;
`
`THAT I have been employed by ImmunoGen, Inc. since 1988, where I hold a position as
`
`Executive Director, Chemistry & Biochemistry, with responsibility for overseeing the research
`
`program on antibody-drug conjugates;
`
`I further declare and state as follows:
`
`I am one of the inventors of the invention described and claimed in the above-identified
`
`application.
`
`
`
`
`
`.___________._‘.___I__~_‘W,mwn_..m.‘~___.mm~m_l,_v_._'_i._'..__.r__.v._
`
`PHIGENIX
`
`Exhibit 1037-00115-
`
`
`
`FIRST DECLARATION UNDER 37 C.F.R. § 1.132
`U.S. Application No.: 10/960,602
`
`Attorney Docket No.: A8662
`
`I am familiar with the above-identified application. In relation thereto I have reviewed
`
`the Office action mailed November 25, 2009, in which claims 1-2, 7-11, 14-17, 20, 23, 26, 29,
`
`35-36, 40-41, 43-44, 47-48, 51-55, 56-57, 60-66, 130, 378, 383—387, 390-393, 396, 399, 402,
`
`405, 411-412, 416-417, 419-420, 423-424, 427-433, 436-442, 447, 452-456, 459-462, 465, 468,
`
`471, 474, 481—482, 484-485, 487-488, 505-506, 511-514, 519—522 and 526-527 are rejected
`
`under 35 U.S.C. 103(a) as being unpatentable over Chari et a1. (US 5,208,020, 1993) in view of
`
`Roguska et 211. (Protein Engineering 1996; 9: 895-904) and Queen et al. (PNAS 1989; 86: 10029-
`
`1 003 3).
`
`In my opinion, one of ordinary skill in the art reading Chari et al. at the time of the
`
`present invention would not have considered modifying an antibody-maytansinoid conjugate
`
`comprising a non-cleavabl'e linker because the teachings of Chari et a1. and the art as of the
`
`October 16, 2003 effective filing date of the present application, taught that conjugates of
`
`cytotoxic drugs with antibodies required the linker to be cleavable for activity, irrespective of the
`
`antibody or the cytotoxic drug used.
`
`My opinion is supported by the following data and teachings of various references as
`
`described below.
`
`The art at the time revealed that conjugates of cytotoxic drugs with antibodies required
`
`the link to be “cleavable” to be active, irrespective of the antibody or the cytotoxic drug used:
`
`See for example: 1) MC Garnett: Adv Drug Delivery Rev., 53; 171-216 (2001); 179, right
`
`column lines 20—23, “A linker which specifically releases drugflom conjugate is therefore a
`
`PHIGENIX
`
`Exhibit 1037-002
`
`
`
`
`
`
`
`FIRST DECLARATION UNDER 37 C.F.R. § 1.132
`US. Application No.: 10/960,602
`
`Attorney Docket No.: A8662
`
`vital component oftargeted drug conjugates”; 2) P. Hermentin & F.R Seller: Behring Inst Min,
`
`82; 197—215 (1988); page 211, conclusion 2 “The anthracycline should be attached to the MoAb
`
`via a spacer that would allow liberation ofdrug” ; 3) R.Chari, Adv Drug Delivery Revs, 31; 89-
`104 (1998); page 93 line 2 second paragraph, “thefullpotency lofthe drug could not be observed
`
`when such non-cleavable linkers were used”.
`
`Thus, the poor potency of non-cleavable mun’ne Antibody-DMl conjugates reported was
`
`consistent with teachings in the art at that time. Antibody—DMI conjugates linked via disulfide
`
`bonds displayed potency in the same range as the free (unconjugated) maytansinoid drugs toward
`
`human tumor cells. For example, see Chan' et al. US Pat No. 5,208,020, Table 3, disulfide-
`
`linked conjugate ICso towards antigen positive cell line range from 2 x 10'10 M (anti-T9-SS-
`
`May/KB) to 4 X 10”” M (A7—SS-May/HT-29), which is in the same range as 1C59 for the parent
`
`unconjugated maytansine drug shown in Table 2 (ICSO ranging from 5 x 10’10 M to 3.4 x 10']1
`
`M). In contrast, the non—cleavable conjugate anti~T9-May is much less potent (ICso = 4 x 10'9 M,
`
`Table 3) than the free maytansine drug.
`
`This data is consistent with a similar comparison made in the art wherein a Vinblastine
`
`drug was linked to an antibody either Via a cleavable hydrazone link or a non—cleavable amide
`
`bond. The authors concluded that the non-cleavable “KSl/4-DAVLB conjugate is 2 orders of
`
`magnitude less potent (emphasis added) than vinblastine sulfate" (the free drug), whereas the
`
`cleavable “KS1/4-DAVLB—HY conjugate is only slightly less potent (emphasis added) than
`
`.._.:..£...,,.,
`
`
`
`
`
`PHIGENIX
`
`- Exhibit 1037-003
`
`
`
`FIRST DECLARATION UNDER 37 CPR. § 1.132
`U.S. Application No.: 10/960,602
`
`Attorney Docket No.: A8662
`
`vinblastine hydrazide” (the parent free drug) (see LS. Johnson et al., Cancer Treatment Revs.,
`
`1987; 14, p 194 lines 13).
`
`Although the non-cleavable murine antibody conjugates in both studies exhibit a small
`
`amount of activity, the potency of non—cleavable murine antibody—DMl conjugates (1050 of 4 x
`
`10'9 M) is in the same range as the non-specific toxicity of non-binding disulfide-linked
`
`antibody—maytansinoid conjugates (1050 of 8 x 10‘9 reported for the non-binding A7—SS-May
`
`conjugate towards KB cells, see Table 3, US Pat No. 5,208,020). There are several other
`
`examples from experiments done in the inventors’ labs showing (Table A) that the potency of
`
`non-binding murine antibody—SS—DMl conjugates (IC50 = 2-8 x 10‘9 M) is in the same range as
`
`the “specific” potency of a non-cleavable murine antibody antiT9—DM1 conjugate (IC50 = 4 x 10"
`
`9) reported in the ‘020 patent. Based on this data, all of the potency of a non-cleavable murine
`
`antibody-DMl conjugate can be attributed to non-specific binding. Thus, because the non—
`
`cleavable murine antibody—DMI conjugate exhibited non~specific levels of potency, and because
`
`the art taught that conjugates of cytotoxic drugs with antibodies required cleavable linkers to be
`
`active, there was no motivation for one of ordinary skill in the art to study non-cleavable
`
`antibody-DMI conjugates.
`
`
`
`
`
`PHIGENIX
`
`Exhibit 1037-004
`
`
`
`FIRST DECLARATION UNDER 37 CPR. § 1.132
`
`Attorney Docket No.: A8662
`
`U.S. Application No.: 10/960,602
`
`Table A: Specific and nonspecific potency ofmurine antibody-DMI conjugates
`
`
`m—
`
`i I);
`ntz‘gerz (+ 3'60? c
`Antigen (— Non binding
`‘nkage
`
`
`
`D.
`isulfide
`.0 x 10'
`(COLO 205
`
`disulfide
`.0 x 10‘ ' (Ramos)
`disulfide
`.0x10' ‘ Ca0v3)
`disulfide
`.0 x10“(HL60)
`Q.
`isulfide
`.7 x 10‘ ' (Calu-3)
`isulfide
`x 10'
`HT—29)
`isulfide
`.0 x 10'
`' (KB
`
`
`
`muT9-DM1*
`
`.5}.
`
`N
`
`6.0 x 10'9(blocked With muB59)
`
`
`
`
`8.0 x 10Tar KB
`2.0 x 10‘
`amalwa
`
`
`cleavable
`
`* data fiom Chari et al. US Pat No. 5,208,020, Table 3
`
`
`
`
`The art at that time also taught that antibody—drug conjugates have to be highly potent to
`
`be therapeutically effective. Conjugates of murine antibodies and three different moderately
`
`cytotoxic drugs (methotrexate, vinblastine and doxorubicin) were tested in human cancer
`
`patients. These conjugates had ICso values in the 10'8 to 10'9 M range (IC50 in the same range as
`
`non-cleavable murine Antibody—DMI conjugates). All three conjugates showed no therapeutic
`
`activity in the clinic and were discontinued.
`
`Conclusions at that time: more potent conjugates needed for therapeutic activity.
`
`1). L. Hinman et al., Cancer Res, 53; 3336—3342 (1993); page 3336, right column lines 11—14,
`
`“An important factor limiting the success of drug-MoAb conjugates is the relatively low potency
`
`of standard chemotherapeutics”. 2). R.Chari, Adv Drug Delivery Revs, 31; 89-104 (1998); page
`
`97 right column lines 10-14
`
`“the shortcomings of early antibody-drug conjugates, namely
`
`moderate potency ——- app ear to have been overcome by newer conjugates centaining drugs that
`
`PHIGENIX
`
`Exhibit 1037-005
`
`
`
`
`
`
`
`FIRST DECLARATION UNDER 37 C.F.R. § 1.132
`- U.S. Application No.: 10/960,602
`
`Attorney Docket No.2 A8662
`
`are 100 to IOOO-fold more potent”. 3). P. Carter, Nature Reviews, 1; 118-129 (2001); page 123
`
`right column: “miniscule portion of injected antibody usually localizes to a solid tumor target.
`
`This is typically 0.001—0.01 % of the injected dose per gram of solid tumor in humans»-
`
`Recognition of this problem inspired the conjugation of small molecule toxins that are 100 to
`
`IOOO—fold more potent than conventional chemotherapeutics”
`
`In view of the above, it is my opinion that as of the October 10, 2003 effective filing date
`
`of the above-identified application, one of ordinary skill in the art would have understood that
`
`the weak potency of non-cleavable murine antibody—DMI conjugates resulted solely from non-
`
`specific antibody binding and no specific potency could be demonstrated. Thus, these non-
`
`cle'avable conjugates of murine antibodies would be considered by one of ordinary skill in the art
`
`to be inactive, and not merely “inferior”, as compared to the free drug or the corresponding
`
`disulfide linked cleavable conjugates. Based on these results and the prevailing teachings in the
`
`art summarized above, there would be no motivation for one of ordinary skill in the art to test
`
`non-cleavable humanized antibody—DMI conjugates.
`
`
`
`PHIGENIX
`
`Exhibit 1037-006
`
`
`
`FIRST DECLARATION UNDER 37 CPR. § 1.132
`U.S. Application No.: 10/960,602
`
`Attorney Docket No.: A8662
`
`I declare further that all statements made herein of my own knowledge are true and that
`
`all statements made on information and belief are believed to be true; and further that these
`
`statements were made with the knowledge that willfifl false statements and the like so made are
`
`punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States
`
`Code, and that such willful false statements may jeopardize the validity of the application or any
`
`patent issuing thereon.
`
`Date: £212 ’1); 1-01?)
`
`lMLL—i
`
`Ravi V. J. Chari, PhD.
`
`
`
`PHIGENIX
`
`Exhibit 1037-007
`
`
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
