(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`23 August 2007 (23.08.2007)
`
`PCT
`
`(10) International Publication Number
`WO 2007/095638 A3
`
`(51) International Patent Classification:
`AOIN 55108 (2006.01)
`A61K 31169 (2006.01)
`
`(21) International Application Number:
`PCT/US2007 /062350
`
`(22) International Filing Date:
`16 February 2007 (16.02.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`601774,532
`60/823,888
`
`16 February 2006 (16.02.2006) US
`29 August 2006 (29.08.2006) US
`
`(71) Applicant (for all designated States except US): ANA(cid:173)
`COR PHARMACEUTICALS, INC. [US/US]; 1060East
`Meadow Circle, Palo Alto, CA 94303-4230 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BAKER, Stephen,
`J. [GB/US]; 1568 Begen Avenue, Mountain View, CA
`94040 (US). SANDERS, Virginia [US/US]; Apt.
`4,
`2895 Harrison Street, San Francisco, CA 94110 (US).
`AKAMA, Tsutomu [JP/US]; 832 Azure Street, Sunny(cid:173)
`vale, CA 94087 (US). BELLINGER-KAWAHARA,
`Carolyn [US/US]; 15 Landa Lane, Redwood City, CA
`94061 (US). FREUND, Yvonne [US/US]; 639 Paco Drive,
`Los Altos, CA 94024 (US). MAPLES, Kirk, R. [US/US];
`1195 San Moritz Drive, San Jose, CA 95132 (US). PLAT(cid:173)
`TNER, Jacob, J. [US/US]; 1016 Ami to Avenue, Berkeley,
`CA 94705 (US). ZHANG, Yong-Kang [US/US]; 5151
`
`Westmont Avenue, San Jose, CA 95130 (US). ZHOU,
`Huchen [CN/US]; Room 1001, Building 10, 50 Youquing
`Road, Shanghai 201100 (CN). HERNANDEZ, Vincent,
`S. [US/US]; 287 Gilchrist Lane, Watsonville, CA 95076
`(US).
`
`(74) Agents: ESKER, Todd et al.; Morgan Lewis & Bockius
`LLP, Suite 700, 2 Palo Alto Square, 3000 El Camino Real,
`Palo Alto, CA 94306 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`with international search report
`
`(88) Date of publication of the international search report:
`31July2008
`
`(54) Title: BORON-CONTAINING SMALL MOLECULES AS ANTI-INFLAMMATORY AGENTS
`
`(57) Abstract: Methods of treating anti-inflammatory conditions through the use of boron-containing small molecules are disclosed.
`
`== -
`
`!!!!!!!!
`
`-iiiiiiii
`iiiiiiii -
`!!!!!!!! -
`
`iiiiiiii
`!!!!!!!!
`
`!!!!!!!!
`iiiiiiii
`
`iiiiiiii ----
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 1 of 149
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/US 07/62350
`
`CLASSIFICATION OF SUBJECT MATTER
`A.
`IPC(8)- A01N 55/08; A61K 31/69 (2008.01)
`USPC- 514/64
`According to International Patent Classification (!PC) or to both national classification and !PC
`
`B.
`
`FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`USPC - 514/64
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`USPC - 514/242, 380; 524/109 (see search terms below)
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`PubWEST(USPT,PGPB,EPAB,JPAB); Google
`Search Terms Used:
`boron therapeutic compounds, Benzoxaborole, boron anti-inflammatory, diarylborinic acid, diazaborinine, cytokine
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category*
`
`Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`y
`
`US 5,880, 188 A (AUSTIN et al.) 09 March 1999 (09.03.1999) col 2, In 15
`
`US 5,962,498 A (DRIEDGER et al.) 05 October 1999 (05.10.1999) abstract; col 6, In 38- 41
`
`US 6,369,098 81 (PERSHADSINGH et al.) 09 April 2002 (09.04.2002) Table IV-VIII
`
`US 2003/0032673 A1 (NAGY) 13 February 2003 (13.02.2003) para [0012)
`
`US 2005/0239170A1 (HEDLEY et al.) 27 October 2005 (27.10.2005) para [0146)
`
`US 2006/0009386 A1 (STOSSEL et al.) 12 January 2006 (12.01.2006) para [0206)
`
`US 5,688,928 A (Stolowitz) 18 November 1997 (18.11.1997) col 5, In 1-10
`
`1-39
`
`1-39
`
`21-22
`
`23-24
`
`25-26
`
`32-34
`
`37-39
`
`D Further documents are listed in the continuation of Box C. D
`•
`Special categories of cited documents:
`later document published after the international filing date or!eriority
`date and not in conflict with the apglication but cited to un erstand
`"A" document defining the general state of the art which is not considered
`the principle or theory underlying t e invention
`to be of particular relevance
`"E" earlier application or patent but published on or after the international "X" document of particular relevance; the claimed invention cannot be
`filing date
`considered novel or cannot be considered to involve an inventive
`step when the document is taken alone
`"L" document which may throw doubts on priority claim(s) or which is
`cited to establish the f!Ublication date of another citation or other "Y" document of particular relevance; the claimed invention cannot be
`special reason (as specified)
`considered to involve an inventive step when the document is
`"O" document referring to an oral disclosure, use, exhibition or other
`combined with one or more other such documents, such combination
`means
`being obvious to a person skilled in the art
`"P" document published prior to the international filing date but later than "&" document member of the same patent family
`the priority date claimed
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`"T'
`
`16 April 2008 (16.04.2008)
`
`Name and mailing address of the ISA/US
`Mail Stop PCT, Attn: ISAIUS, Commissioner for Patents
`P.O. Box 1450, Alexandria, Virginia 22313-1450
`Facsimile No. 571-273-3201
`
`Form PCTIISN2 I 0 (second sheet) (April 2007)
`
`16 MAY 2008
`
`Authorized officer:
`
`LeeW. Young
`
`PCT Helpdesk: 571-272-4300
`PCT OSP: 571-272-7774
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 2 of 149
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/US 07/62350
`
`This application contains the following inventions or groups of inventions, which are not so linked as to form a single general
`inventive concept under the PCT Rule 13.1. In order for all inventions to be examined, the appropriate additional fees must
`be paid.
`
`[In claim 8, formula VI is written as 'IV', this is treated as 'VI']
`
`Group I, claims 1-11, 13-36 are drawn to a method of treating an inflammatory related disease in a human or an animal, said
`method comprising administering to the human or animal a therapeutically erfective amount of a compound (e.g. formula I,
`111.IV,V.VI).
`
`Group II. claims 1-2, 12. 17. 19. 2 I, 23, 25, 27, 29, 3 1-32, 34-35 are drawn to a method of treating an inflammatory related
`disease in a human or an animal, said method comprising administering to the human or the animal a therapeutically effective
`amount of a compound (e.g. a compound in claim 12, which is having 616 fused ring system different from the 5/6 ring
`system present in other formulas).
`
`Group Ill, claims 37-39 are drawn to a method of treating an inflammatory related disease in a human or an animal, said
`method comprising administering to the human or the animal a therapeutically effective amount of a compound having a
`structure according to formula 11.
`
`I. This International Searching Authority considers that the international application does not comply with the requirements of unity of
`invention (Rules 13.1. 13.2 and 13.3) for the reasons indicated below:
`There is no significant common structural element in the compounds of Groups 1-111. For instance -0- (e.g. formula I , claim
`1 ) is known. and thus clearly is not a contribution over the art. Thus, no special technical feature exists among the Groups,
`and hence Groups 1-111 lack unity of invention.
`
`Group I is distinct from he other Groups because the latter do not require a compound of formula Ill, IV, V or VI.
`
`Group II is distinct from the other Groups because the latter do not require a compound as claimed in claim 12.
`
`Group Ill is distinct from the other Groups because the latter do not require a compound of formula II.
`
`Form PCT/JSA/210 (extra sheet) (April 2007)
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 3 of 149
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`PCT/US 07/62350
`
`Box No. II
`
`Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)
`
`This international search report has not been established in respect of certain claims under Article l 7(2)(a) for the following reasons:
`
`I. D Claims Nos.:
`
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`2. 0 Claims Nos.:
`
`because they relate to parts of the international application that do not comply with the prescribed requirements to such an
`extent that no meaningful international search can be carried out, specifically:
`
`3. 0 Claims Nos.:
`
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
`
`Il?~s J:c\~~~~~gpal Searching Authority found multiple inventions in this international application, as follows:
`
`I. IZI
`2. D
`3. D
`
`4. D
`
`As all required additional search fees were timely paid by the applicant, this international search report covers all searchable
`claims.
`
`As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of
`additional fees.
`
`As only some of the required additional search fees were timely paid by the applicant, this international search report covers
`only those claims for which fees were paid, specifically claims Nos.:
`
`No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention fust mentioned in the claims; it is covered by claims Nos.:
`
`Remark on Protest
`
`D
`D
`IZI
`
`The additional search fees were accompanied by the applicant's protest and, where applicable, the
`payment ofa protest fee.
`The additional search fees were accompanied by the applicant's protest but the applicable protest
`fee was not paid within the time limit specified in the invitation.
`No protest accompanied the payment of additional search fees.
`
`Form PCT/ISA/210 (continuation of first sheet (2)) (April 2007)
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 4 of 149
`
`

`

`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`I lllll llllllll II llllll lllll lllll lllll llll I II Ill lllll lllll lllll 111111111111111111111111111111111
`
`( 43) International Publication Date
`23 August 2007 (23.08.2007)
`
`PCT
`
`(10) International Publication Number
`WO 2007/095638 A2
`
`(51) International Patent Classification:
`
`Not classified
`
`(21) International Application Number:
`PCT/US2007 /062350
`
`(22) International Filing Date:
`16 February 2007 (16.02.2007)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`601774,532
`60/823,888
`
`16 February 2006 (16.02.2006) US
`29 August 2006 (29.08.2006) US
`
`(71) Applicant (for all designated States except US): ANA(cid:173)
`COR PHARMACEUTICALS, INC. [US/US]; 1060East
`Meadow Circle, Palo Alto, CA 94303-4230 (US).
`
`Road, Shanghai 201100 (CN). HERNANDEZ, Vincent,
`S. [US/US]; 287 Gilchrist Lane, Watsonville, CA 95076
`(US).
`
`(74) Agents: ESKER, Todd et al.; Morgan Lewis & Bockius
`LLP, Suite 700, 2 Palo Alto Square, 3000 El Camino Real,
`Palo Alto, CA 94306 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, Fl,
`GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS,
`JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS,
`LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MY,
`MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS,
`RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN,
`TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`without international search report and to be republished
`upon receipt of that report
`
`For two-letter codes and other abbreviations, refer to the "Guid(cid:173)
`ance Notes on Codes and Abbreviations" appearing at the begin(cid:173)
`ning of each regular issue of the PCT Gazette.
`
`(57) Abstract: Methods of treating anti-inflammatory conditions through the use of boron-containing small molecules are disclosed.
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BAKER, Stephen,
`J. [GB/US]; 1568 Begen Avenue, Mountain View, CA
`94040 (US). SANDERS, Virginia [US/US]; Apt.
`4,
`2895 Harrison Street, San Francisco, CA 94110 (US).
`AKAMA, Tsutomu [JP/US]; 832 Azure Street, Sunny(cid:173)
`vale, CA 94087 (US). BELLINGER-KAWAHARA,
`Carolyn [US/US]; 15 Landa Lane, Redwood City, CA
`94061 (US). FREUND, Yvonne [US/US]; 639 Paco Drive,
`Los Altos, CA 94024 (US). MAPLES, Kirk, R. [US/US];
`1195 San Moritz Drive, San Jose, CA 95132 (US). PLAT(cid:173)
`TNER, Jacob, J. [US/US]; 1016 Ami to Avenue, Berkeley,
`CA 94705 (US). ZHANG, Yong-Kang [US/US]; 5151
`Westmont Avenue, San Jose, CA 95130 (US). ZHOU,
`Huchen [CN/US]; Room 1001, Building 10, 50 Youquing
`
`!!!!!!!!
`
`iiiiiiii
`!!!!!!!!
`
`iiiiiiii
`
`-iiiiiiii
`iiiiiiii -
`!!!!!!!! -
`= (54) Title: BORON-CONTAINING SMALL MOLECULES AS ANTI-INFLAMMATORY AGENTS
`----
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 5 of 149
`
`

`

`WO 2007/095638
`
`PCT /US2007 /062350
`
`BORON-CONTAINING SMALL MOLECULES AS ANTI-INFLAMMATORY
`AGENTS
`
`CROSS-REFERENCE TO RELATED APPLICATIONS
`
`[0001] This application claims priority to United States Provisional Patent
`
`Application Serial Nos. 60/823,888 filed on August 29, 2006 and 60/774,532 filed on
`
`February 16, 2006, which are herein incorporated by reference in its entirety for all
`
`purposes.
`
`BACKGROUND FOR THE INVENTION
`
`[0002]
`
`Irregular inflammation is a major component of a wide range of human
`
`diseases. People suffering from degenerative disorders often exhibit excess levels of
`
`pro-inflammatory regulators in their blood. One type of such pro-inflammatory
`
`regulators are cytokines including IL-la, ~' IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17,
`
`IL-18, IL-23, TNF-a, LT, LIF, Oncostatin, and IFNcla, ~, y.
`
`[0003]
`
`A non-limiting list of common medical problems that are directly caused
`
`by inflammatory cytokines include: arthritis where inflammatory cytokines can lead
`
`to lesions in the synovial membrane and destruction of joint cartilage and bone;
`
`kidney failure where inflammatory cytokines restrict circulation and damage
`
`nephrons; lupus where inflammatory cytokines exacerbate immune complex
`
`deposition and damage; asthma where inflammatory cytokines close the airway;
`
`psoriasis where inflammatory cytokines induce dermatitis; pancreatitis where
`
`inflammatory cytokines induce pancreatic cell injury; allergy where inflammatory
`
`cytokines induce vasopermeability and congestion; fibrosis where inflammatory
`
`cytokines attack traumatized tissue; surgical complications where inflammatory
`
`cytokines prevent healing; anemia where inflammatory cytokines attack
`
`erythropoietin production; and fibromyalgia where inflammatory cytokines are
`
`elevated in fibromyalgia patients.
`
`[0004]
`
`Other diseases associated with chronic inflammation include cancer; heart
`
`attack where chronic inflammation contributes to coronary atherosclerosis;
`
`Alzheimer's disease where chronic inflammation destroys brain cells; congestive heart
`
`failure where chronic inflammation causes heart muscle wasting; stroke where
`
`chronic inflammation promotes thrombo-embolic events; and aortic valve stenosis
`
`1
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 6 of 149
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`

`

`WO 2007/095638
`
`PCT /US2007 /062350
`
`where chronic inflammation damages heart valves. Arteriosclerosis, osteoporosis,
`
`Parkinson's disease, infection, inflammatory bowel disease including Crohn's disease
`
`and ulcerative colitis as well as multiple sclerosis (a typical autoimmune
`
`inflammatory-related disease) are also related to inflammation (Bebo, B. F., Jr., J
`
`Neurosci Res, 45: 340-348, (1996); Mennicken, F., Trends Pharmacol Sci, 20: 73-78,
`
`(1999); Watanabe, T, Int J Cardiol, 66 Suppl 1: S45-53; discussion S55, (1998);
`
`Sullivan, G. W., J Leukoc Biol, 67: 591-602, (2000); Franceschi, C., Ann NY Acad
`
`Sci, 908: 244-254, (2000); Rogers, J, Ann NY Acad Sci, 924: 132-135, (2000); Li, Y.
`
`J., Hum Mol Genet, 12: 3259-3267, (2003); Maccarrone, M., Curr Drug Targets
`
`Injlamm Allergy, 1: 53-63, (2002); Lindsberg, P. J., Stroke, 34: 2518-2532, (2003);
`
`DeGraba, T. J., Adv Neural, 92: 29-42, (2003);. Ito, H., Curr Drug Targets Injlamm
`
`Allergy, 2: 125-130, (2003); von der Thusen, J. H., Pharmacol Rev, 55: 133-166,
`
`(2003); Schmidt, M. I.,. Clin Chem Lab Med, 41: 1120-1130, (2003); Virdis, A., Curr
`
`Opin Nephrol Hypertens, 12: 181-187, (2003); Tracy, R. P., Int J Clin Pract, Suppl
`
`10-17, (2003); Haugeberg, G., Curr Opin Rheumatol, 15: 469-475, (2003); Tanaka,
`
`Y., J Bone Miner Metab, 21: 61-66, (2003); Williams, J. D., Clin Exp Dermatol, 27:
`
`585-590, (2002)). Some diseases in advanced stages can be life threatening. Several
`
`methodologies are available for the treatment of such inflammatory diseases; the
`
`results, however, are generally unsatisfactory as evidenced by a lack of efficacy and
`
`drug related side effects associated therewith.
`
`Inflammatory Bowel Disease
`
`[0005]
`
`Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and
`
`ulcerative colitis (UC), both of which are idiopathic chronic diseases occurring with
`
`an increasing frequency in many parts of the world. In the United States, more than
`
`600,000 are affected every year. IBD can involve either small bowel, large bowel, or
`
`both. CD can involve any part of the gastrointestinal tract, but most frequently
`
`involves the distal small bowel and colon. It either spares the rectum, or causes
`
`inflammation or infection with drainage around the rectum. UC usually causes ulcers
`
`in the lower part of the large intestine, often starting at the rectum. Symptoms vary
`
`but may include diarrhea, fever, and pain. Patients with prolonged UC are at an
`
`increased risk of developing colon cancer. There is currently no satisfactory
`
`treatment, as the cause for IBD remains unclear although infectious and immunologic
`
`mechanisms have been proposed. IBD treatments aim at controlling inflammatory
`
`2
`
`CFAD v. Anacor, IPR2015-01776, CFAD EXHIBIT 1063 - Page 7 of 149
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`

`

`WO 2007/095638
`
`PCT /US2007 /062350
`
`symptoms, conventionally using corticosteroids, aminosalicylates and standard
`
`immunosuppressive agents such as azathioprine (6-mercaptopurine), methotrexate and
`
`ciclosporine. Of these, the only disease-modifying therapies are the
`
`immunosuppressive agents azathioprine and methotrexate, both of which have a slow
`
`onset of action and only a moderate efficacy. Long-term therapy may cause liver
`
`damage (fibrosis or cirrhosis) and bone marrow suppression. Also patients often
`
`become refractory to such treatment. Other therapeutic regimes merely address
`
`symptoms (Rutgeerts, P. A, J Gastroenterol Hepatol, 17 Suppl: SI 76-185 (2002);
`
`Rutgeerts, P., Aliment Pharmacol Ther, 17: 185-192 (2003)).
`
`Psoriasis
`
`[0006]
`
`Psoriasis is one of the most common immune-mediated chronic skin
`
`diseases that comes in different forms and varied levels of severity, affecting
`
`approximately 2% of the population or more than 4.5 million people in the United
`
`States of which 1.5 million are considered to have a moderate to severe form of the
`
`disease. Ten to thirty percent of patients with psoriasis also develop a form of
`
`arthritis--psoriatic arthritis, which damages the bone and connective tissue around the
`
`joints. Psoriasis appears as patches of raised red skin covered by a flaky white
`
`buildup. It may also have a pimple-ish (pustular psoriasis) or burned ( erythrodermic)
`
`appearance. Psoriasis may also cause intense itching and burning. Patients suffer
`
`psychologically as well as physically. Several modalities are currently available for
`
`treatment of psoriasis, including topical treatment, phototherapy, and systemic
`
`applications. However, they are generally considered to be only disease suppressive
`
`and disease modifying; none of them are curative. Moreover, many treatments are
`
`either cosmetically undesirable, inconvenient for long-term use, or associated with
`
`significant toxicity.
`
`[0007] With increased understanding of the biological properties of psoriasis over
`
`the past two decades, biologic therapies targeting the activity of T lymphocytes and
`
`cytokines responsible for the inflammatory nature of this disease have become
`
`available. Currently, drugs prescribed for psoriasis include TNF-a inhibitors initially
`
`used for rheumatoid arthritis (RA) treatment, ENBREL® ( etanercept), REMICADE®
`
`(infliximab) and HUMIRA® ( adalimumab ), and T-cell inhibitor AMEVIVE®
`
`( alefacept) from Biogen approved in 2002 and RAPTIV A® ( efalizumab) from
`
`Genentech/Xoma approved in 2003 (Weinberg, J. M., J Drugs Dermatol, 1: 303-310,
`
`3
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`(2002)). AMEVIVE ALEF ACEPT® is an immunoglobulin fusion protein composed
`
`of the first extracellular domain of human LFA-3 fused to the hinge, C(H)2 and
`
`C(H)3 domains of human IgG(I). It inhibits T cell proliferation through NK cells
`
`(Cooper, J.C., Eur J Immunol, 33: 666-675, (2003)). RAPTIVA® is also known as
`
`anti-CD I Ia, a humanized monoclonal antibody which targets the T cell adhesion
`
`molecule, leukocyte function-associated antigen-I (LFA-I). Prevention ofLFA-I
`
`binding to its ligand (ICAM-I, intercellular adhesion molecule-I) inhibits lymphocyte
`
`activation and migration, resulting in a decreased lymphocyte infiltration, thereby
`
`limiting the cascade of events eventually leading to the signs and symptoms of
`
`psoriasis (Cather, J.C., Expert Opin Biol Ther, 3: 36I-370, (2003)). Potential side
`
`effects for current TNF-a inhibitors of the prior art, however, are severe, including
`
`development oflymphoma (Brown, S. L., Arthritis Rheum, 46: 3I5I-3I58, (2002)),
`
`worsening congestive heart failure, resulting in a serious infection and sepsis, and
`
`exacerbations of multiple sclerosis and central nervous system problems (Weisman,
`
`M. H.,. J Rheumatol Suppl, 65: 33-38, (2002); Antoni, C., Clin Exp Rheumatol, 20:
`
`SI52-I57, (2002)). While side effects of the T-cell inhibitor of
`
`AMEVIVE®/RAPTIV A® may be more tolerable in psoriasis treatment, RAPTIV A®
`
`is an immunosuppressive agent. Immunosuppressive agents have the potential to
`
`increase the risk of infection, reactivate latent, chronic infections or increase the risk
`
`of cancer development.
`
`[0008]
`
`Although many advances have been made in the understanding of the
`
`biological properties of psoriasis over the past two decades and an unconventional
`
`treatment for psoriasis has become available as described above, much of the
`
`suffering it produces is still not adequately addressed. A survey of over 40,000
`
`American patients with psoriasis performed by the National Psoriasis Foundation in
`
`I 998 showed 79% of the younger patients felt frustrated by the ineffectiveness of
`
`their treatment. Of those with severe disease, 32% felt their treatment was not
`
`aggressive enough (Mendonca, C. 0., Pharmacol Ther, 99: 133-I47, (2003); Schon,
`
`M. P., J Invest Dermatol, I I2: 405-410, (I999)).
`
`Rheumatoid Arthritis
`
`[0009]
`
`Rheumatoid arthritis (RA) represents another example of troublesome
`
`inflammatory disorders. It is a common chronic inflammatory-related disease
`
`characterized by chronic inflammation in the membrane lining (the synovium) of the
`
`4
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`joints and/or other internal organs. The inflammatory cells can also invade and
`
`damage bone and cartilage. The joint involved can lose its shape and alignment,
`
`resulting in loss of movement. Patients with RA have pain, stiffness, warmth, redness
`
`and swelling in the joint, and other systemic symptoms like fever, fatigue, and
`
`anemia. Approximately 1 % of the population or 2.1 million in the U.S. are currently
`
`affected, of which more are women (1.5 million) than men (0.6 million). The
`
`pathology of RA is not fully understood although the cascade of improper
`
`immunological reactions has been postulated as a mechanism. Conventional
`
`treatment is unfortunately inefficient in RA (Bessis, N., J Gene Med, 4: 581-591,
`
`(2002)) (29). The disease does not respond completely to symptomatic medications
`
`including corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) used
`
`since the 1950s. Also, these medications carry a risk of serious adverse effects. The
`
`therapeutic effects of the disease-modifying antirheumatic drugs (DMARDs) such as
`
`Methotrexate (MTX) are often inconsistent and short-lived.
`
`[0010]
`
`A new class of biologic DMARDs (disease-modifying antirheumatic
`
`drugs) for the treatment of RA has recently been developed based on an
`
`understanding of the role of cytokines, TNF-a and IL-1, in the inflammatory process.
`
`The FDA has approved several such DMARDs including ENBREL® ( etanercept)
`
`from Immunex/ Amgen Inc. in 1998, REMICADE® (infliximab) from
`
`Centocor/Johnson & Johnson, HUMIRA® ( adalimumab) from Abbott Laboratories
`
`Inc. in 2002, and KINERET® ( anakinra) from Amgen in 2001. ENBREL® is a
`
`soluble TNF receptor (TNFR) recombinant protein. REMICADE® is a humanized
`
`mouse (chimeric) anti-TNF-a monoclonal antibody. HUMIRA® is a fully human
`
`anti-TNF monoclonal antibody created using phage display technology resulting in an
`
`antibody with human-derived heavy and light chain variable regions and human
`
`IgG 1 :k constant regions. All these 3 protein-based drugs target and bind to TNF-a to
`
`block the effects of TNF-a. KINERET® is a recombinant IL-1 receptor antagonist,
`
`which is similar to native human IL-1 Ra, except for the addition of a single
`
`methionine residue at its amino terminus. KINERET® blocks the biologic activity of
`
`IL-1 by competitively inhibiting IL-1 binding to the IL-1 type I receptor (IL-lRI) and
`
`consequently reducing the pro-inflammatory effects of IL-1.
`
`[0011]
`
`The treatment with these biologic DMARDs relieves symptoms, inhibits
`
`the progression of structural damage, and improves physical function in patients with
`
`5
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`moderate to severe active RA. The three marketed TNF-a blocking agents have
`
`similar efficacy when combined with MTX, a widely used DMARD, in the treatment
`
`of patients with RA (Hochberg, M. C., Ann Rheum Dis, 62 Suppl 2: ii13-16, (2003)).
`
`While providing significant efficacy and a good overall safety profile in the short and
`
`medium term in many patients with RA, these biologic treatments may create serious
`
`problems and long-term side effects, such as in the liver, and still need to be
`
`evaluated. There has been a disturbing association between the use of both of
`
`ENBREL® or REMICADE® and the development oflymphoma, (S. L., Arthritis
`
`Rheum, 46: 3151-3158, (2002)). As described above, several reports have shown that
`
`patients treated with ENBREL® or REMICADE® worsen their congestive heart
`
`failure and develop serious infection and sepsis, and increase exacerbations of
`
`multiple sclerosis and other central nervous system problems (Antoni, C., Clin Exp
`
`Rheumatol, 20: S152-157, (2002); Mendonca, C. 0., Pharmacol Ther, 99: 133-147,
`
`(2003)).
`
`Multiple Sclerosis
`
`[0012]
`
`Multiple Sclerosis (MS) is an autoimmune disease diagnosed in 350,000 to
`
`500,000 people in the United States. Multiple areas of inflammation and loss of
`
`myelin in the brain and spinal cord signify the disease. Patients with MS exhibit
`
`varied degrees of neurological impairment depending on the location and extent of the
`
`loss of the myelin. Common symptoms of MS include fatigue, weakness, spasticity,
`
`balance problems, bladder and bowel problems, numbness, vision loss, tremors and
`
`depression. Current treatment of MS only alleviates symptoms or delays the
`
`progression of disability, and several new treatments for MS including stem cell
`
`transplantation and gene therapy are conservatory (Fassas, A., Blood Rev, 17: 233-
`
`240, (2003); Furlan, R., Curr Pharm Des, 9: 2002-2008, (2003)). While anti-TNF
`
`antibodies have shown protective effects in experimental autoimmune
`
`encephalomyelitis (EAE), they aggravate the disease in MS patients, suggesting that
`
`inhibition of TNF-a alone is not sufficient (Ghezzi, P., Neuroimmunomodulation, 9:
`
`178-182, (2001)).
`
`Neurodegenerative Disorders
`
`[0013]
`
`Alzheimer's disease (AD) and Parkinson's disease (PK) are the two most
`
`common neurodegenerative disorders. AD seriously affects a person's ability to carry
`
`out daily activities. It involves the parts of the brain that control thought, memory,
`
`6
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`and language. About 4 million Americans, usually after age 60, are estimated to
`
`suffer from AD.
`
`[0014]
`
`PK is a progressive disorder of the central nervous system affecting over
`
`1.5 million people in the United States. Clinically, the disease is characterized by a
`
`decrease in spontaneous movements, gait difficulty, postural instability, rigidity and
`
`tremor. PK is caused by the degeneration of the pigmented neurons in the substantia
`
`nigra of the brain, resulting in decreased dopamine availability. The causes of these
`
`neurodegenerative disorders are unknown and there is currently no cure for the
`
`disease.
`
`[0015]
`
`Thus, novel approaches for the treatment of the above and other
`
`inflammatory-related diseases are needed. Although inflammatory-related disease
`
`mechanisms remain unclear and often vary from each other, dysfunction of the
`
`immune system caused by deregulation of cytokines has been demonstrated to play an
`
`important role in the initiation and progression of inflammation (Schon, M. P., J
`
`Invest Dermatol, 112: 405-410, (1999); Andreakos, E.T., Cytokine Growth Factor
`
`Rev, 13: 299-313, (2002); Najarian, D. J., J Am Acad Dermatol, 48: 805-821, (2003)).
`
`[0016]
`
`Cytokines can be generally classified into 3 types: pro-inflammatory (IL-
`
`la, ~, IL-2, IL-3, IL-6, IL-7, IL-9, IL-12, IL-17, IL-18, IL-23, TNF-a, LT, LIF,
`
`Oncostatin, and IFNcla, ~' y); anti-inflammatory (IL-4, IL-10, IL-11, W-13 and TGF(cid:173)
`
`~); and chemokines (IL-8, Gro-a, MIP-1, MCP-1, ENA-78, and RANTES).
`
`[0017]
`
`In many inflammatory conditions, pro-inflammatory cytokines, especially
`
`TNF-a, IL-1~, and IL-6, as well as anti-inflammatory cytokine IL-10 appear to play
`
`an important role in the pathogenesis of various inf