Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 1 of 62 PageID #: 1366
`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 1 of 62 PageID #: 1366
`
`EXHIBIT 60
`
`EXHIBIT 6O
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 2 of 62 PageID #: 1367
`
` 
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`ARIOSA DIAGNOSTICS
`
`Petitioner,
`
`v.
`
`VERINATA HEALTH, INC.
`
`Patent Owner.
`
`____________
`
`IPR2013- _____
`
`Patent 8,318,430
`
`____________
`
`FIRST PETITION FOR INTER PARTES REVIEW
`UNDER 35 U.S.C. §§ 311–319 AND 37 C.F.R. § 42.100 ET SEQ.
`(CLAIMS 1-18)
`
`
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 3 of 62 PageID #: 1368
`
` 
`
`TABLE OF CONTENTS
`
`TABLE OF CONTENTS ............................................................................................ i 
`
`EXHIBIT LIST ........................................................................................................ iii 
`
`I. 
`
`INTRODUCTION ........................................................................................... 1 
`
`II.  MANDATORY NOTICES ............................................................................. 3 
`A.  Real Party-In-Interest....................................................................................... 3 
`B.  Related Matters ................................................................................................ 3 
`C.  Lead and Back-Up Counsel ............................................................................. 4 
`D.  Service Information ......................................................................................... 4 
`
`III. 
`
`PAYMENT OF FEES ..................................................................................... 4 
`
`IV.  REQUIREMENTS FOR INTER PARTES REVIEW ...................................... 5 
`A.  Grounds for Standing ....................................................................................... 5 
`B.  Identification of Challenge .............................................................................. 5 
`1. The Specific Art and Statutory Ground(s) on Which the Challenge Is
`Based ......................................................................................................... 5 
`2. How the Construed Claims Are Unpatentable under the Statutory Grounds
`Identified in 37 C.F.R. § 42.204(B)(2) and Supporting Evidence Relied
`upon to Support the Challenge ................................................................. 6 
`
`FACTUAL BACKGROUND .......................................................................... 7 
`V. 
`A.  Declaration Evidence ....................................................................................... 7 
`B.  The State of the Art ........................................................................................ 10 
`C.  The Prosecution History of the ‘430 Patent (issuing from Application No.
`13/368,035) .................................................................................................... 11 
`
`VI.  BROADEST REASONABLE CONSTRUCTION ....................................... 12 
`A.  “Selectively enriching” .................................................................................. 13 
`B.  “Sequence reads corresponding to enriched and indexed fetal and maternal
`non-random polynucleotide sequences” ........................................................ 14 
`C.  “Reference chromosome” .............................................................................. 15 
`
`
` 
`
`i
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 4 of 62 PageID #: 1369
`
` 
`
`VII. GROUNDS OF INVALIDITY ...................................................................... 16 
`A. Claims 1-18 Are Rendered Obvious by Dhallan Taken in Combination with
`Binladen ......................................................................................................... 16 
`B. Claims 1-18 Are Rendered Obvious by Quake Taken in Combination with
`Craig .............................................................................................................. 29 
`C. Claims 1-18 Are Rendered Obvious by Shoemaker Taken in Combination
`with Dhallan and Binladen ............................................................................ 40 
`
`VIII.  CONCLUSION .............................................................................................. 56 
`
`
`
`ii
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 5 of 62 PageID #: 1370
`
` 
`
`1001
`1002
`1003
`1004
`1005
`1006
`1007
`1008
`1009
`
`EXHIBIT LIST
`
`
`
`
`
` 
`U.S. Patent No. 8,318,430 to Chuu, et al.
`Declaration of Prof. Cynthia Morton
`Declaration of Prof. Robert Nussbaum
`Dhallan, U.S. Pat No. 7,332,277
`Binladen, et al., PLoS One. 2(2):e197 (2007)
`Quake, et al., U.S. Pat. Pub. 2007/0202525
`Craig et al. Nat Methods 5(10): 887–893 (2008)
`Shoemaker, et al., U.S. Pat. Pub. US 2008/0090239
`Joint Claim Construction Statement from Verinata Health, Inc.
`et al. v. Ariosa Diagnostics, Inc. et al., Case No. 3:12-cv-
`05501-SI (N.D. Cal)
`
`iii
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 6 of 62 PageID #: 1371
`
` 
`
`I.
`
`INTRODUCTION
`
`Petitioner Ariosa Diagnostics, Inc. (“Ariosa” or “Petitioner”) respectfully
`
`requests inter partes review of claims 1-18 of U.S. Patent No. 8,318,430 in
`
`accordance with 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42.100 et seq. On even
`
`date herewith Ariosa is filing a separate petition requesting inter partes review of
`
`the remaining claims of the ‘430 patent.
`
`The ‘430 patent is generally directed to a sample multiplexing method for
`
`detecting fetal aneuploidies by counting, in a maternal blood sample, the number
`
`of DNA fragments from a chromosome suspected of being aneuploid and the
`
`number of fragments from a non-aneuploid chromosome. (Morton Dec.¶30) The
`
`two numbers are compared to determine whether there is an abnormal level of
`
`DNA associated with the chromosome suspected of being aneuploid. (Morton
`
`Dec. ¶30) This method is performed for a plurality of maternal blood samples
`
`using indexing techniques to distinguish results from different samples. (Morton
`
`Dec. ¶30)
`
`The USPTO allowed the ‘430 patent on the basis that the prior art of record
`
`was not believed to teach or suggest the use of “massively parallel sequencing” to
`
`“selectively enrich a plurality of non-random polynucleotide sequences of each
`
`fetal and maternal cell-free genomic DNA sample." (NOA, p. 7)
`
`
`
`
`
`1
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 7 of 62 PageID #: 1372
`
` 
`
`However, several references which were among the hundreds of cited
`
`references (but which were not discussed during prosecution) plainly disclose the
`
`use of various sequencing techniques on maternal and fetal extracellular DNA.
`
`U.S. Patent No. 7,332,277 to Dhallan, U.S. Pat. Pub. 2007/0202525 to Quake, and
`
`U.S. Pat. Pub. US 2008/0090239 to Shoemaker are three such references. As
`
`explained in the declarations of Professor Nussbaum and Professor Morton,
`
`Dhallan, Quake and Shoemaker use sequencing techniques on maternal and fetal
`
`DNA. Dhallan, Quake and Shoemaker render the claimed subject matter obvious
`
`when considered in light of then-conventional techniques for indexing sequence
`
`reads when using massively parallel sequencing, as exemplified by Binladen, et al.,
`
`PLoS One. 2(2):e197 (2007) and Craig et al. Nat Methods 5(10): 887–893 (2008).
`
`Neither Craig nor Binladen were cited or considered in the prosecution of the ‘430
`
`patent.
`
`The references, claim charts and declaration evidence presented herewith
`
`demonstrate that claims 1-18 of the ‘430 patent are rendered obvious by the
`
`various combinations of prior art discussed below.
`
`
`
`
`
`2
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 8 of 62 PageID #: 1373
`
` 
`
`II. MANDATORY NOTICES
`Pursuant to 37 C.F.R. § 42.8(a)(1), Petitioner provides the following
`
`mandatory disclosures.
`
`A. Real Party-In-Interest
`Pursuant to 37 C.F.R. § 42.8(b)(1), Petitioner certifies that Ariosa
`
`Diagnostics, Inc. is the real party-in-interest.
`
`B. Related Matters
`Pursuant to 37 C.F.R. § 42.8(b)(2), Petitioner states that the ‘430 Patent is
`
`the subject of litigation captioned Verinata Health, Inc. et al. v. Ariosa
`
`Diagnostics, Inc. et al., Case No. 3:12-cv-05501-SI (N.D. Cal).
`
`On even date herewith Petitioner is filing a second petition for inter partes
`
`review which is directed to claims 19-30 of the ‘430 patent. The primary difference
`
`between the two sets of claims is that independent claim 1 recites use of a
`
`“reference chromosome” whereas independent claim 19 recites use of a
`
`“chromosome control region.”
`
`Petitioner also intends to file in the coming days a petition for inter partes
`
`review directed to related U.S. Patent No. 8,296,076, which is also at issue in the
`
`above-captioned litigation.
`
`
`
`
`
`
`
`3
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 9 of 62 PageID #: 1374
`
` 
`
`
`
`C. Lead and Back-Up Counsel
`
`Pursuant to 37 C.F.R. § 42.8(b)(3), Petitioner provides the following
`
`designation of counsel: Lead counsel is Greg Gardella (Reg. No. 46,045) and
`
`back-up counsel are Scott A. McKeown (Reg. No. 42,866) and Kevin B. Laurence
`
`(Reg. No. 38,219).
`
`Service Information
`
`D.
`Pursuant to 37 C.F.R. § 42.8(b)(4), papers concerning this matter should be
`
`served on the following.
`
`Email:
`
`Address: Greg Gardella, Scott McKeown or Kevin Laurence
`Oblon Spivak
`1940 Duke Street
`Alexandria, VA 22314
`cpdocketgardella@oblon.com
`cpdocketmckeown@oblon.com and
`cpdocketlaurence@oblon.com
`
`Telephone: (703) 413-3000
`Fax:
`
`(703) 413-2220
`
`
`
`III. PAYMENT OF FEES
`
`The undersigned authorizes the Office to charge to Deposit Account No. 15-
`
`0030 the fee required by 37 C.F.R. § 42.15(a) for this Petition for inter partes
`
`review. The undersigned further authorizes payment for any additional fees that
`
`might be due in connection with this Petition to be charged to the above referenced
`
`Deposit Account.
`
`
`
`
`
`4
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 10 of 62 PageID #: 1375
`
` 
`
`IV. REQUIREMENTS FOR INTER PARTES REVIEW
`
`As set forth below and pursuant to 37 C.F.R. § 42.104, each requirement for
`
`inter partes review of the ‘430 patent is satisfied.
`
`A. Grounds for Standing
`Pursuant to 37 C.F.R. § 42.104(a), Petitioner hereby certifies that the ‘430
`
`patent is available for inter partes review and that the Petitioner is not barred or
`
`estopped from requesting inter partes review challenging the claims of the ‘430
`
`patent on the grounds identified herein.
`
`B. Identification of Challenge
`Pursuant to 37 C.F.R. §§ 42.104(b) and (b)(1), Petitioner requests inter
`
`partes review of claims 1-18 of the ‘430 patent, and that the Patent Trial and
`
`Appeal Board (“PTAB”) invalidate the same.
`
`1.
`
`The Specific Art and Statutory Ground(s) on Which the
`Challenge Is Based
`
`
`
`Pursuant to 37 C.F.R. § 42.104(b)(2), inter partes review of the ‘430 patent
`
`is requested in view of the following references, each of which is prior art to the
`
`‘430 patent under 35 U.S.C. § 102 (a), (b), and/or (e):
`
` (1) Dhallan, U.S. Pat No. 7,332,277 (issued Feb. 19, 2008) and Binladen, et
`
`al., PLoS One. 2(2):e197 (2007) render obvious claims 1-18.
`
` (2) Quake, et al., U.S. Pat. Pub. 2007/0202525 (pub. Aug. 30, 2007) and
`
`Craig et al. Nat Methods 5(10): 887–893 (Oct. 2008) render claims 1-18 obvious.
`
`5
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 11 of 62 PageID #: 1376
`
` 
`
`(3) Shoemaker, et al., U.S. Pat. Pub. US 2008/0090239 (pub. Apr. 17,
`
`2008), Dhallan, U.S. Pat No. 7,332,277 (issued Feb. 19, 2008), and Binladen, et
`
`al., PLoS One. 2(2):e197 (2007) render obvious claims 1-18.
`
`2.
`
`How the Construed Claims Are Unpatentable under the
`Statutory Grounds Identified in 37 C.F.R. § 42.204(B)(2)
`and Supporting Evidence Relied upon to Support the
`Challenge
`
`
` Pursuant to 37 C.F.R. § 42.104(b)(4), an explanation of how claims 1-18 of
`
`the ‘430 patent are unpatentable under the statutory grounds identified above,
`
`including the identification of where each element of the claim is found in the prior
`
`art, is provided in Section VII, below, in the form of claim charts. Pursuant to 37
`
`C.F.R. § 42.104(b)(5), the exhibit numbers of the supporting evidence relied upon
`
`to support the challenges and the relevance of the evidence to the challenges
`
`raised, including identifying specific portions of the evidence that support the
`
`challenges, are provided in Section VII below, in the form of claim charts.
`
`
`
`
`
`
`6
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 12 of 62 PageID #: 1377
`
` 
`
`V.
`
`FACTUAL BACKGROUND
`A. Declaration Evidence
`This Petition is supported by the Declaration of Professor Morton from
`
`Harvard University. (Ex. 1002, “Morton Declaration”) and by the Declaration of
`
`Professor Robert Nussbaum from the University of California at San Francisco
`
`(Ex. 1003; “Nussbaum Declaration”). Each offers various opinions with respect
`
`to the scope and content of the prior art.
`
`Prof. Morton currently holds the William Lambert Richardson Professorship
`
`in the Department of Obstetrics, Gynecology and Reproductive Biology at Harvard
`
`Medical School and is also a professor in the Department of Pathology at Harvard
`
`Medical School. She is Director of Cytogenetics at Brigham and Women's
`
`Hospital. She received her B.S. in Biology from The College of William and Mary
`
`and her Ph.D. in Human Genetics from the Medical College of Virginia. She is
`
`board-certified by the American Board of Medical Genetics in PhD Medical
`
`Genetics, Clinical Cytogenetics and Clinical Molecular Genetics and has received
`
`numerous awards including the Warner-Lambert/Parke-Davis Award of the
`
`American Society of Investigative Pathology. She is the recent past Editor of The
`
`American Journal of Human Genetics and serves/has served on the Editorial
`
`Boards of the American Journal of Medical Genetics, Genomics, Journal of
`
`Experimental Zoology, Genes, Chromosomes and Cancer, American Journal of
`
`7
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 13 of 62 PageID #: 1378
`
` 
`
`Human Genetics, Human Genetics, International Journal of Clinical and
`
`Experimental Pathology, The Application of Clinical Genetics, Audiology and
`
`Neurotology, International Journal of Women’s Health, and Cancer Management
`
`and Research. She served as an editor of the book Current Protocols in Human
`
`Genetics and has contributed fourteen book chapters. She sits on various
`
`scientific/medical committees, including the Board of Directors of the American
`
`Society of Human Genetics, the Council of Scientific Trustees of the Hearing
`
`Health Foundation and the Genomic Medicine Program Advisory Committee for
`
`the Veteran's Administration. She is the senior author on a recent publication of
`
`the first use of whole genome sequencing in the prenatal setting for diagnosis of a
`
`genetic syndrome (N. Engl. J. Med., 367:2226-32 (2012)). Prof. Morton has
`
`published over 260 peer-reviewed manuscripts in the field of obstetrics,
`
`reproductive biology, auditory science and human medical genetics and authored
`
`over 280 abstracts presented at various scientific meetings worldwide.
`
`
`
`Prof. Nussbaum is the Holly Smith Distinguished Professor of Medicine and
`
`Chief of the Division of Genomic Medicine in the Department of Medicine at the
`
`University of California, San Francisco and a member of the UCSF Institute of
`
`Human Genetics. He received his A. B. from Harvard College in 1971 and his M.D.
`
`from the Harvard-MIT Joint Program in Health Sciences and Technology. He
`
`studied Internal Medicine at Washington University & Barnes Hospital and Medical
`
`8
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 14 of 62 PageID #: 1379
`
` 
`
`Genetics at the Baylor College of Medicine. He is familiar with DNA sequencing
`
`technology including massively parallel DNA sequencing methods, which are used
`
`for determining genetic characteristics or for detecting genetic disorders, and has
`
`published numerous scientific papers and lectured extensively on human genetics.
`
` He is board-certified by the American Board of Internal Medicine, and by the
`
`American Board of Medical Genetics in Clinical Genetics and Clinical Molecular
`
`Genetics. Prof. Nussbaum has received numerous awards including the 2011 Klaus
`
`Joachim Zülch Neuroscience Prize granted by the Gertrud Reemtsma Foundation
`
`for his contribution to neuroscience research in Parkinson’s disease.
`
`Dr. Nussbaum is an author on nearly 200 peer-reviewed manuscripts in the
`
`field of human genetics and disease and is an author and editor of Thompson &
`
`Thompson Genetics in Medicine, 6th Edition, which is a review of the basic
`
`principles of medical genetics, recent advances in molecular genetics, and the
`
`clinical applications of this new knowledge for the diagnosis and management of
`
`genetic disorders. This textbook is used widely by medical students, genetic
`
`counselors, and other medical practitioners as a definitive reference on medical
`
`genetics.
`
`Prof. Nussbaum serves/has served on the Editorial Boards of the American
`
`Journal of Human Genetics, Cytogenetics and Cell Genetics, Human Genetics,
`
`Journal of Clinical Investigation, Human Molecular Genetics, American Journal of
`
`9
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 15 of 62 PageID #: 1380
`
` 
`
`Medical Genetics, Functional and Integrative Genomics, Journal of Clinical
`
`Investigation, and Genome Medicine. From 1997-2003, Prof. Nussbaum served as
`
`Editor-in-Chief of Human Genetics (for Asia and Americas) and from 2006 to the
`
`present as Section Editor for Genetics in Medicine. He has participated on various
`
`scientific/medical committees, including as Head of the Clinical Molecular
`
`Genetics Training Program at the National Human Genome Research Institute
`
`(NHGRI).
`
`B. The State of the Art
`
`
`
`By 2008 it was well established that blood plasma and serum from pregnant
`
`women contained cell-free DNA from both the mother and fetus in relatively high
`
`concentrations. (Ex. 1001, 1:20-37; Morton Declaration at ¶20-23, Nussbaum
`
`Declaration at ¶24-25). Numerous methods for detecting fetal DNA in a plasma
`
`or serum sample from a pregnant woman for identifying genetic abnormalities in
`
`the fetus were known. (Ex. 1001, 1:20-37; Morton Declaration ¶22-24; Nussbaum
`
`Declaration ¶¶24-25) Methods for determining whether a fetus had an abnormal
`
`chromosome number (aneuploidy) by comparing the amounts of DNA fragments
`
`originating from an aneuploid chromosome and a normal chromosome had been
`
`widely published. (Morton Declaration at ¶¶24-26 and Nussbaum Declaration at
`
`¶¶26-28).
`
`10
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 16 of 62 PageID #: 1381
`
` 
`
`
`
`Massively parallel sequencing methods were in routine use by 2008. These
`
`methods permitted the rapid sequencing of nucleic acids including those
`
`constituting the entire human genome or portions of it. (Ex. 1001 at 10:7-27;
`
`Morton Declaration at ¶¶ 16-17; and Nussbaum Declaration at ¶¶19-23).
`
`
`
`Multiplexed massively parallel sequencing of a pooled sample (e.g.,
`
`efficiently sequencing a mixed or pooled sample containing the DNA fragments
`
`from several different individuals after indexing the DNA fragments from each
`
`individual with a tag or barcode unique to a sample) were also well known and in
`
`widespread use as of 2010. (Morton Declaration at ¶¶ 17-19; and Nussbaum
`
`Declaration at ¶¶19-23).
`
`C. The Prosecution History of the ‘430 Patent (issuing from
`Application No. 13/368,035)
`
` 
`
`
`
`The ‘035 application was filed on February 7, 2012. The original claims
`
`were rejected under 35 U.S.C. 102(b) over Roland, et al., U.S. 2008/0070792 on
`
`March 13, 2012. In response, the applicants made various amendments to the
`
`claims after which the Examiner issued a new obviousness rejection based on US
`
`2007/0202525 to Quake and an Illumina 2008 publication (“Illumina”). (Final OA,
`
`pp. 3-8) The applicants submitted argument in response to the final rejection and
`
`the Examiner responded with a Notice of Allowance. The accompanying
`
`statement of reasons for allowance indicated that “2007/0202525 does not teach or
`
`11
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 17 of 62 PageID #: 1382
`
` 
`
`suggest ‘b) selectively enriching a plurality of non-random polynucleotide
`
`sequences of each fetal and maternal cell-free genomic DNA sample’ in
`
`conjunction with the use of massively parallel sequencing.” (NOA, p. 7)
`
`
`VI. BROADEST REASONABLE CONSTRUCTION
`
`Petitioner bases this petition upon the broadest reasonable interpretation of
`
`the claim language. Petitioner’s position regarding the scope of the claims under
`
`their broadest reasonable interpretation is not to be taken as stating any position
`
`regarding the appropriate scope to be given the claims in a court or other
`
`adjudicative body under the different claim interpretation standards that may apply
`
`to such proceedings.
`
`Petitioner has included herewith for the Board’s reference the Joint Claim
`
`Construction Statement from Verinata Health, Inc. et al. v. Ariosa Diagnostics,
`
`Inc. et al., Case No. 3:12-cv-05501-SI (N.D. Cal). (Exhibit 1009)
`
`All claimed terms not specifically addressed in this section have been
`
`accorded their broadest reasonable interpretation in light of the patent specification
`
`including their plain and ordinary meaning.  
`
` 
`
`12
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 18 of 62 PageID #: 1383
`
` 
`
`
`
`A.  “Selectively enriching”
`
`The term “selectively enriching” is not explicitly defined by the
`
`specification. The term “selective enrichment” of nucleic acids from a sample
`
`encompasses, under the broadest reasonable interpretation, increasing the
`
`concentration of a selected subset of nucleic acids relative to the remainder of the
`
`nucleic acids in the sample.
`
`This phrase is used, for example, in the specification at Col. 2, lines 40-43:
`
`In another embodiment, said selectively enriching comprises
`performing PCR. In another embodiment, said selectively enriching
`comprises linear amplification.
`
`In this passage, the phrase “selectively enriching” embodies a method that
`
`selectively increases the relative concentration of a selected DNA region by
`
`amplification methods. The experimental section of the specification describes
`
`only selective amplification by PCR for enrichment to create multiple copies of a
`
`sequence such as a “hot spot.” (Ex. 1001, 14:59-22:41) Besides amplification, the
`
`‘430 patent mentions no other methods that could be used for selective enrichment.
`
`(Morton Declaration ¶31; Nussbaum Declaration ¶30-31) Hot spots are selected
`
`regions in the genome, as described in Example 1 of the ‘430 patent. (Morton
`
`Declaration ¶31; Nussbaum Declaration ¶31) As explained in the declaration of
`
`Prof. Nussbaum, under the broadest reasonable interpretation, a person in the field
`
`of medical genetics would interpret “selective enrichment” as taught in the ‘430
`
`13
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 19 of 62 PageID #: 1384
`
` 
`
`to include increasing the concentration of a selected molecule in a sample
`
`relative to other molecules of the sample. (Nussbaum Dec., ¶¶30-31) This
`
`interpretation would encompass selective amplification of the DNA of genomic
`
`regions because selective amplification results in an increased number of copies of
`
`the selected DNA relative to other genomic regions. (Morton Dec., ¶¶9 and 31;
`
`Nussbaum Dec., ¶¶31-32)
`
`B. “Sequence reads corresponding to enriched and indexed fetal and
`maternal non-random polynucleotide sequences”
` 
`
` 
`
`
`
`The ‘430 specification describes “sequence reads” as information obtained
`
`by sequencing selectively enriched products from a sample, as exemplified below:
`
`In one aspect, a method for determining the presence or absence of
`fetal aneuploidy is provided comprising a) selectively enriching non-
`random polynucleotide sequences of genomic DNA from a cell-free
`DNA sample; b) sequencing said enriched polynucleotide sequences;
`c) enumerating sequence reads from said sequencing step; and d)
`determining the presence or absence of fetal aneuploidy based on said
`enumerating. (Ex. 1001, 1:40-48)
`
`
`
`As the only sequence reads taught in the ‘430 are the product of sequencing
`
`selectively enriched polynucleotides, the term “sequence reads” is interpreted to
`
`include the order of bases determined for enriched polynucleotides. (Morton
`
`Declaration ¶31-32, Nussbaum Declaration ¶35) Importantly, the use of
`
`“sequence” in this particular term refers to information rather than a physical
`
`14
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 20 of 62 PageID #: 1385
`
` 
`
`molecule. (Id.). This interpretation encompasses a determined order of nucleotide
`
`arrangements (i.e., “sequence”) from a selectively enriched and indexed
`
`polynucleotide molecule from a maternal cell-free nucleic acid sample. (Id.).
`
`The term “non-random polynucleotide sequence” is interpreted to include
`
`a nucleic acid molecule that has been selectively enriched, such as one that is
`
`amplified by PCR using primers that amplify a specific DNA region in a genome.
`
`(Morton Declaration ¶32, Nussbaum Declaration ¶32) The use of “sequence” in
`
`this term refers to a physical molecule, as it describes a molecule resulting from a
`
`selective enrichment procedure, e.g., a physical copy of a non-random DNA
`
`region.
`
`In light of the foregoing, the term “sequence reads corresponding to
`
`enriched and indexed fetal and maternal non-random polynucleotide
`
`sequences” is construed under the broadest interpretation as including the result
`
`of determining the order of nucleotides from sequencing selectively enriched
`
`and indexed polynucleotides. (Morton Declaration ¶32, Nussbaum Declaration
`
`¶35)
`
`C. “Reference chromosome”
`
`
`
`In the specification, the term “reference chromosome” is used to describe
`
`chromosomes that can actually serve as comparators to a chromosome being tested
`
`for aneuploidy. (Ex. 1001, 2:10-11, 13:6-8, 13:62-63, 19:18-19, 20:58-89, Figs.
`
`15
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 21 of 62 PageID #: 1386
`
` 
`
`8B, 16 and 17) In order for such a comparison to be meaningful, the reference
`
`chromosome must be a chromosome that is not itself being tested for aneuploidy.
`
`(Nussbaum Declaration, ¶33) Therefore, this term has been construed as including
`
`a chromosome that is not being tested for aneuploidy and which is presumed
`
`prior to testing to be diploid. (Nussbaum Declaration, ¶33-34).
`
`
`
`Petitioner notes that this interpretation of the term “reference chromosome”
`
`is consistent with the interpretation of the related term “chromosome control
`
`region” set forth in the additional petition discussed in Section II.B, above.
`
`
`
`VII. GROUNDS OF INVALIDITY
`
`The references reviewed below render obvious the claimed subject matter
`
`under 35 U.S.C. §103. The Petitioner has a reasonable likelihood of prevailing as
`
`to each of the following grounds of invalidity.
`
`
`
`A. Claims 1-18 Are Rendered Obvious by Dhallan Taken in
`Combination with Binladen
`U.S. Patent No. 7,332,277 to Dhallan (“Dhallan”, Ex. 1004) is cited on the
`
`face of the ‘430 patent; however, it was not applied in any rejection during
`
`prosecution of the ‘430 patent and is not cumulative of any prior art specifically
`
`applied by the examiner during examination. Binladen, et al. (“Binladen”, Ex.
`
`1005) was not considered during the prosecution of the ‘430 patent.
`
`16
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 22 of 62 PageID #: 1387
`
` 
`
`As explained in the Declarations of Profs. Nussbaum and Morton, a skilled
`
`artisan would have considered the processes described in claims 1-18 obvious in
`
`view of Dhallan and the conventional indexed techniques for determining sequence
`
`reads as described in Binladen. (Nussbaum Declaration ¶¶36-76: Morton
`
`Declaration ¶¶34-65) A scientist in this field would have had strong incentive to
`
`combine these techniques because doing so would clearly result in enhanced
`
`productivity and increased throughput of sample analysis. (Nussbaum Declaration
`
`¶36)
`
`Correspondence to
`Dhallan, US Patent No. 7,332,277 and Binladen et al, PLoS one, 2(2):e197
`
`1. A method for
`determining a presence
`or absence of a fetal
`aneuploidy in a fetus
`
`for each of a plurality
`of maternal blood
`samples obtained from
`a plurality of different
`pregnant women,
`
`“The method is especially useful for detection of a
`translocation, addition, amplification, transversion,
`inversion, aneuploidy, polyploidy, monosomy, trisomy,
`trisomy 21, trisomy 13, trisomy 14, trisomy 15, trisomy
`16, trisomy 18, trisomy 22, triploidy, tetraploidy, and sex
`chromosome abnormalities including but not limited to
`XO, XXY, XYY, and XXX.” (Dhallan 25:63-26:6)
`“Currently, the method provides a means for the
`simultaneous sequencing, generation of single molecule
`sequences, and assignment of short (120 bp) from
`homologous PCR products obtained from multiple
`individuals.” (Binladen at 2:2:7-10)
`See Declarations of Prof. Nussbaum at ¶¶36-37 and Prof.
`Morton at ¶¶34-35.
`“Fetal DNA has been detected and quantitated in maternal
`plasma and serum (Lo et al., Lancet 350:485-487 (1997);
`Lo et al., Am. J. hum. Genet. 62:768-775 (1998)).”
`(Dhallan, 5:39-41)
`“Blood samples were received from 27 different clinical
`
`17
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 23 of 62 PageID #: 1388
`
` 
`
`sites operating in 16 different states located throughout
`the U.S.” (Dhallan, 219:57-63)
`See also Binladen at Abstract, lines 4-7 and 2:2:7-10.
`See Declarations of Prof. Nussbaum at ¶¶36-37 and Prof.
`Morton at ¶36.
`“In another embodiment, the template DNA is obtained
`from the plasma or serum of the blood of the pregnant
`female. The percentage of fetal DNA in maternal plasma
`is between 0.39-11.9% (Pertl, and Bianchi, Obstetrics and
`Gynecology 98: 483-490 (2001)).” (Dhallan, 32:22-25)
`See Declarations of Prof. Nussbaum at ¶¶36-37 and Prof.
`Morton at ¶37.
`“In another embodiment, the template DNA is obtained
`from the plasma or serum of the blood of the pregnant
`female. The percentage of fetal DNA in maternal plasma
`is between 0.39-11.9% (Pertl, and Bianchi, Obstetrics and
`Gynecology 98: 483-490 (2001)).” (Dhallan, 32:22-25)
`“Blood samples were received from 27 different clinical
`sites. . .” (Dhallan, 219:57-63)
`“Currently, the method provides a means for the
`simultaneous sequencing, generation of single molecule
`sequences, and assignment of short (,120 bp) from
`homologous PCR products obtained from multiple
`individuals.” (Binladen, 2:2:7-10)
`Binladen teaches the use of DNA from a plurality of
`individuals at Fig. 1.
`See Declarations of Prof. Nussbaum at ¶¶38-39 and Prof.
`Morton at ¶38.
`“The template DNA [maternal and fetal DNA] can be
`amplified using any suitable method known in the art
`including but not limited to PCR (polymerase chain
`reaction).” (Dhallan, 47:38-40)
`See Declarations of Prof. Nussbaum at ¶¶40-45 and Prof.
`Morton at ¶39.
`
`said maternal blood
`samples comprising
`fetal and maternal cell-
`free genomic DNA,
`said method
`comprising:
`
`(a) obtaining a fetal
`and maternal cell-free
`genomic DNA sample
`from each of the
`plurality of maternal
`blood samples;
`
`(b) selectively
`enriching a plurality of
`non-random
`polynucleotide
`sequences of each fetal
`and maternal cell-free
`genomic DNA sample
`
`18
`
`

`

`Case 1:20-cv-01644-RGA Document 1-60 Filed 12/03/20 Page 24 of 62 PageID #: 1389
`
` 
`
`of (a)
`to generate a library
`derived from each fetal
`and maternal cell-free
`genomic DNA sample
`of enriched and
`indexed fetal and
`maternal non-random
`polynucleotide
`sequences,
`
`wherein each library of
`enriched and indexed
`fetal and maternal non-
`random polynucleotide
`sequences includes an
`indexing nucleotide
`sequence which
`identifies a maternal
`blood sample of the
`plurality of maternal
`blood samples,
`wherein said plurality
`of non-random
`polynucleotide
`sequences comprises at
`least 100 different non-
`random polynucleotide
`sequences selected
`from a first
`chromosome test