Petitioner Demonstrative Exhibits
`
`Case IPR2013‐00390
`
`August 5, 2014
`
`1
`
`1
`
`SEQUENOM EXHIBIT 1106
`Sequenom v. Stanford
`IPR2013-00390
`
`

`

`{11}
`
`United States Patent
`Fan et al.
`
`net Petenl Hm:
`
`HS) Date of Patent:
`
`US 3,195,415 B2
`Jun. 5, 2012
`
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`Subject tn any disclaimer, Ihe term nl‘thie
`patent is extended er adjusted under 35
`H.511 154th by El days.
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`Int. L'I.
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`ILEfl'l'Hi-fll]
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`............... ........ . ................ TDII'?l;435.-'I5.1
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`Field ufE‘llHificlliun Search
`THEN RE—l R5, TI: 1.15m
`See applicatien file fer cempiete search liietery.
`
`Heierencei tilted
`
`US. PATENT DOCUMENTS
`
`Disclt'ised is El melhnd In achieve digital quantification nl'
`DNA (i.e..ceuntittg.difle:ettce5 between identical sequences]-
`ueing direel sitetguu sequencing lullewecl by Limp-ping tn tltc
`uhrtumemme Ur urigin and untu'nerutiun Ui- l-rugnumle [her
`elimn'neunte. The preferred mell'tud uses mileeiuely purulle]
`sequencing. which enn pmduee lens {if millinne nf 5hrn1
`sequence mgsinneittye t'lltt-t'lll-ti eneblingueunpling therein:
`be statistically e-uluetee. Hy muntittg 111:: number ul‘
`swuenee tugs mapped m u predefu'ied Windtiw in eueh chm-
`meeume, 1he u-rer- L'll' under-reprwenlulien 111' any cluumu-
`name in malernal pleelue UNA ennu-ihuled by un aneupini-Li
`I'elur: can he detected. 'l'ttic Jiiellmtl the: net require tlte tlif-
`ferenlieljettet'ietel venue metemnl DN.’t.1'nemetlieneeunl
`ul' uutueumul values ie used mi u neimulixutien cunetent tu
`
`ueeeunt fur differeueee itt tutu] number ul' sequence Leg; 'Ili
`
`Ex. 1001
`
`

`

`Grounds of Unpatentability
`
`3
`
`Paper 1, p. 4
`Paper 7, pp. 3, 21-22
`
`

`

`Claim Construction
`
`4
`
`Paper 7, p. 7
`
`

`

`.i‘t. methnd nf testing fer an nbnnrmnl distributinn nf at
`1.
`specified chrnmnsnme I'lfll'llflfl in n mittecl sumple nl‘nnrmnll].r
`21nd ebnnrinelly distributed clirninnsnnie pnrtinns nhtnined
`i'rnm ti subject. cnmprising:
`{e} sequencing DNA [mm the mixed etimple In nbtein
`sequences frnm multiple chrnmnsnme pnrtinns. wherein
`suid sequences cnniprisc at number nl‘ sequence tags nl”
`sufltcient length nt' detenninecl sequence tn be assigned
`tn 3 chrnmnsnme Inestinn within at gennme'.
`[b] assigning the sequence tags tn cnrrespnnding chrnmn—
`sume pettinits including HI least the specified Eill'UfllU-
`snnte by ccnipeiing the detenninetl sequence ct" the
`scqucncc tegs tn :- rct'crcncc gcnnnnc sequence:
`[cl determining vnlues fer ntnnbers nt" sequence tugs map—
`ping tn chrnmnsnme pnrtinns by using n number nf
`
`windnws nl' dellned length within nnrntull}t end nhnur-
`mnlly distributed cln'nmnsnme pusrtinns tn nbtnin n first
`value end at scennd wtlue therelnun: and
`
`5
`{d} using the values li'ntn step {c} tn determine at dilleren-
`tittl. between the lirst value and the secnnd ‘c'ttltttt'. which
`
`is detemiinntice nF whether nr net the ebnnrmnl distri-
`
`Ex. 1001,
`Claim 1
`
`

`

`13. a, luctltnd nt‘ dctcnuining nit nhnanunlly distributed
`cltnuuusutue punitin al' interest in a "tit-ted sample ttl' nur-
`mall},t and flh-I'Ifll'lflfllljt' distributed l—JHJ‘t intilcculcs. entupris-
`ing:
`{a} sequencing DNA in said sample by ntassis'elj.r parallel
`Sequencing tn chtain a ntunlser cut" sequence tags
`{it} mart-ping said sequence tags tn specific cltrnlunsrrme
`Istrtiu-ns. each chrumusuiuai panic-n being eeluprised in
`a sliding windnw cfa predetermined length;
`{e} detenuining numbers tifseqttenee tugs mapped In each
`sliding wiuduw an at least each autnsetue'.
`{d} determining a mean cl said numbers Fur each aulu same
`and a seen-11d mean Fur at least all autu-suiues:
`
`tfc} calculating a nnnnalised value train all autasantcs,
`using said seeend mean; and
`{fl cnnipnring nnrmnliscd 1entities nmnng nutnsnntcs tn
`determine any abnamially distributed autasnmal citra-
`6
`ntusutuc punitin al' interest.
`
`Ex. 1001,
`Claim 13
`
`

`

`“Windows” and “Sliding Window”
`
`Claim 1
`
`Claim 13
`
`7
`
`

`

`Broadest Reasonable Interpretation of 
`“Window”
`
`Paper 7, p. 8
`
`Interference No. 105,922
`Ex. 1088, p. 18
`
`8
`
`

`

`Broadest Reasonable Interpretation of 
`“Sliding Window”
`
`Paper 7, p. 9
`
`9
`
`

`

`“Equal Length” Cannot Be Read Into ‘415 
`Patent Claims Absent Clear Intention to 
`Limit
`
`10
`
`Interference No. 105,922
`Ex. 1088, p. 16
`
`

`

`Lone Reference to Equal Length Does Not 
`Establish Clear Intention to Limit
`
`Ex. 1001, 4:53-64
`
`• No rationale for Patent Owner’s assertion that “This is explained
`in detail below” refers specifically to single sentence at end of
`paragraph rather than the ensuing 16 pages of the specification
`
`• Last sentence of paragraph presents equal length windows as an
`option for improving results, not a requirement
`
`11
`
`

`

`Example 8 Utilizes Two Different Size 
`Windows in the Same Experiment
`
`*****
`
`12
`
`Ex. 1001, 26:7-45
`
`

`

`Dr. Fan Confirms That Trisomy Detection and 
`GC Bias Measurement Within a Sample Set 
`Constitutes a Single Experiment
`
`Ex. 1089, 107:17-108:20
`
`13
`
`

`

`Windows Have Uses Other Than 
`Normalization
`
`14
`
`Interference No. 105,922
`Ex. 1088, p. 14
`
`

`

`Dr. Detter Testified That Windows Have 
`Uses Other Than Normalization
`
`15
`
`Ex. 2117, ¶41
`Ex. 1087, ¶45
`
`

`

`Board Has Twice Determined That Lo II 
`Discloses Windows
`
`Paper 7, pp.
`10-11
`
`Interference No.
`105,922
`Ex. 1088,
`pp. 18-19
`
`16
`
`

`

`Patent Owner’s Assertion That Lo II 
`Chromosomal Regions are Not Windows 
`Lacks Merit
`
`• Patent Owner argues Lo II chromosomal regions are not
`windows because they “are not defined by size” and “may
`vary from person to person”
`
`• However, ‘415 Patent states that window size is arbitrary:
`
`Ex. 1001, 5:6-11
`
`17
`
`

`

`Patent Owner’s Assertion That Lo II 
`Chromosomal Regions are Not Windows 
`Lacks Merit
`
`• Patent Owner argues Lo II chromosomal regions are not windows
`because they represent “a polynucleotide sequence whose
`imbalance is itself being tested” rather than a tool being used to
`do that testing
`
`• However, Lo II explicitly states that a “clinically relevant
`chromosomal region”:
`
`• Dr. Gabriel testified that windows can themselves may be tested
`for aneuploidy (Ex. 2001, 56:17-20, 57:15-19)
`
`Ex. 1002, ¶¶0037, 0052
`
`18
`
`

`

`Patent Owner Fails to Apply Wands Factors 
`in Asserting Undue Experimentation
`
`• Patent Owner asserts Lo II does not enable windows because
`it lacks working examples and sufficient guidance (Paper 24,
`pp. 19-21)
`
`• Working examples not required for enablement (In re
`Borkowski, 422 F.2d 904, 908 (C.C.P.A. 1970)
`
`• The disclosure of Lo II enables windows in view of the full
`range of Wands factors, including level of skill in the art,
`nature of the invention, state of the prior art, and level of
`predictability in the art
`• Level of skill in the art was high
`• Windows were conventional statistical tools used in
`sequencing
`
`19
`
`

`

`Drs. Gabriel and Detter Agree That the 
`Level of Skill in the Art Was High
`
`Ex. 1010, ¶0022
`
`Ex. 2117, ¶0018
`
`20
`
`

`

`Drs. Gabriel and Detter Agree That 
`Windows Were a Conventional Statistical 
`Tool in Sequencing
`
`• Dr. Gabriel testified that using windows to correct for non-
`uniform distribution of sequence tags and G/C bias was a
`conventional statistical data analysis technique (Ex. 1010,
`¶28)
`
`• Dr. Detter admits that windows were conventional and
`standard tools in bioinformatics:
`
`21
`
`Ex. 1090, 12:4-10
`
`

`

`Prior Art Confirms Conventional Use of 
`Windows in Sequencing
`
`• Lander (Ex. 1101, p. 876, right col., 3rd full ¶ to p. 877, left col.,
`4th full ¶; p. 884, left col., 1st full ¶; Figs. 9, 13, 22, 36)
`
`• Shimkets (Ex. 1004, ¶0007)
`
`• Margulies (Ex. 1091, p. 3356, right col., 1st full ¶)
`
`• Giladi (Ex. 1092, Abstract)
`
`• Fares (Ex. 1093, Abstract, p. 512, ¶ spanning columns)
`
`• Brickner (Ex. 1094, Abstract, p. 96, 3rd full ¶)
`
`22
`
`

`

`Patent Owner Fails to Antedate Lo II
`
`• Burden is on Patent Owner to establish corroborated
`conception and actual reduction to practice
`
`• Patent Owner relies heavily on testimony and unsigned,
`unwitnessed laboratory notebooks of Dr. Fan
`
`• Declaration of co-inventor Dr. Quake withdrawn for failure
`to testify
`
`• No testimony from Chu, Fischer, Chitkara, Hudgins, Sidow,
`Shi, Neff, White, Ingolia, or Herzenberg (all coauthors and
`alleged collaborators)
`
`• Third party testimony (Drs. DeRisi, Blumenfeld, Detter) and
`proffered emails do not corroborate the alleged prior
`invention
`
`23
`
`

`

`Dr. DeRisi Fails to Corroborate Fan’s 
`Alleged Prior Invention
`• Testified that his laboratory performed sequencing runs in
`2008 on behalf of Drs. Fan and Quake (Ex. 2135, ¶¶3-6)
`• Not involved in actual development of aneuploidy
`detection method
`
`• Testimony and emails (Ex. 2119-2126, 2128) cited as
`corroboration of alleged actual reduction to practice
`• Emails do not mention aneuploidy detection or use of
`windows
`• No indication from Dr. DeRisi or other 3rd party
`correspondents (Chu, Fischer) that they were aware of
`conception or reduction to practice
`• Testimony merely states that his laboratory performed
`sequencing
`• No discussion of specific claim steps, much less a
`statement that he was aware of an actual reduction to
`practice
`
`24
`
`

`

`Dr. Blumenfeld Fails to Corroborate Fan’s 
`Alleged Prior Invention
`• Testified that he collaborated with inventors from end of 2006
`to 2008 (Ex. 2134, ¶6)
`• Provided blood samples and prepared protocol and
`consent forms for IRB
`• Not involved in actual development of aneuploidy
`detection method
`
`• Testimony and emails cited as corroboration of alleged actual
`reduction to practice
`• Testimony merely restates contents of his emails
`• No explanation of his one word email response
`“Awesome!” (Ex. 2127)
`• No mention of specific claim steps, much less a statement
`that he was aware of an actual reduction to practice
`• No confirmation that proffered email attachments are the
`same ones that were included with original emails
`
`25
`
`

`

`Proffered Blumenfeld Emails Fail to 
`Corroborate Fan’s Alleged Prior Invention
`• Emails with data attachments (Ex. 2127, 2129) do not provide
`explanation of attached data or discuss the specific steps of the
`‘415 Patent claims
`• Dr. Blumenfeld has not testified as to what he actually knew
`or understood at the time, and does not explain his one word
`exclamation (“awesome!”) in Ex. 2127 (Ex. 2134, ¶8)
`• No evidence that attachments are the same ones included
`with original emails
`
`• Emails regarding manuscripts (Ex. 2111-2113, 2131) insufficient
`to corroborate in the absence of relevant third party testimony
`• Emails do not mention the method steps, and Dr. Blumenfeld
`has not testified as to what he actually knew or understood at
`the time (Ex. 2134, ¶9)
`• No testimony from other involved authors/collaborators
`• No evidence that manuscripts are the same ones included
`with original emails
`
`26
`
`

`

`Dr. Detter Cannot Corroborate Fan’s 
`Alleged Prior Invention
`
`• Testified about the state of the art in 2008 and the inventors’
`mindset and activities (Ex. 2117, ¶¶25-29; Ex. 2138, ¶¶4-5)
`• Acknowledges having no previous contact with inventors
`(Ex. 1090, 15:17-18, 20:8-22:10)
`• Admits that he relied entirely on material provided by
`Patent Owner and did not perform a prior art search (Ex.
`1090, 15:19-17:18, 61:7-64:3)
`
`• Testimony cited as corroboration of actual reduction to
`practice
`• Only non-inventor declarant to specifically mention actual
`reduction to practice, but admits that he does not know
`what an actual reduction to practice is (Ex. 1090, 18:9-
`20:7, 22:12-24:10, 25:17-26:8)
`
`27
`
`

`

`“Sliding Window” Claims 13 and 16 Are 
`Obvious Over Lo II and Wang
`• Wang discloses the use of “sliding windows,” which had a clear
`meaning in the art:
`
`Ex. 1005, p. 16157,
`left col., 1st ¶
`
`Ex. 1005, p. 16159,
`right col., 1st full ¶
`
`28
`
`Ex. 1005, p. 16159, ¶
`spanning columns
`
`Ex. 1005, Fig. 2
`legend
`
`

`

`“Sliding Window” Claims 13 and 16 Are 
`Obvious Over Lo II and Wang
`• Dr. Detter admits that sliding windows have been standard and
`conventional statistical tools for normalizing data since at least
`1999:
`
`Ex. 1090, 12:4-10
`• Lo II combined with Wang renders claims 13 and 16 obvious
`because the claims do not require equal length sliding windows
`
`• Wang shows that windows do not need to be of equal length for
`normalization (Ex. 1005, p. 16157, left col., 1st ¶; Fig. 2 legend)
`
`29
`
`

`

`“One Mismatch” Claim 17 is Obvious Over 
`Lo II, Wang, Hillier, and/or Smith
`
`• Wang’s exclusion of sequence tags corresponding to
`polymorphisms at the tag site would not discourage one of
`ordinary skill in the art from allowing for mismatches in an MPS
`method
`
`• Wang used 1st generation Sanger sequencing -— low error rates
`
`• MPS had high error rates in 2008, POSITA would recognize
`exclusion of mismatches impractical
`
`• High error rates and alignment of mismatches explicitly
`disclosed in Smith and Hillier (Ex. 1009, p. 2, right col., 1st ¶; Ex.
`1006, p. 185, Fig. 2)
`
`• Drs. Fan and Detter acknowledge ELAND could align sequences
`with one mismatch (Ex. 1089, 51:23-55:18; Ex. 1090, 117:23-
`119:19)
`
`30
`
`