Association For Molecular Pathology et al v. United States Patent and Trademark Office et al
COUNTER STATEMENT TO 154 Rule 56.1 Statement. Document filed by American Society For Clinical Pathology, College of American Pathologists, Association For Molecular Pathology, Haig Kazazian, Arupa Ganguly, Wendy Chung, Harry Ostrer, David Ledbetter, Stephen Warren, Ellen Matloff, Elsa Reich, Breast Cancer Action, Boston Women's Health Book Collective, American College of Medical Genetics, Lisbeth Ceriani, Runi Limary, Genae Girard, Patrice Fortune, Vicky Thomason, Kathleen Raker. (Hansen, Christopher)
Association For Molecular Pathology et al v. United States Patent and Trademark Office et al
UNITED STATES DISTRICT COURT SOUTHERN DISTRICT OF NEW YORK --------------------------------------------------------------------------x ASSOCIATION FOR MOLECULAR PATHOLOGY; AMERICAN COLLEGE OF MEDICAL GENETICS; AMERICAN SOCIETY FOR CLINICAL PATHOLOGY; COLLEGE OF AMERICAN PATHOLOGISTS; HAIG KAZAZIAN, MD; ARUPA GANGULY, PhD; WENDY CHUNG, MD, PhD; HARRY OSTRER, MD; DAVID LEDBETTER, PhD; STEPHEN WARREN, PhD; ELLEN MATLOFF, M.S.; ELSA REICH, M.S.; BREAST CANCER ACTION; BOSTON WOMEN'S HEALTH BOOK COLLECTIVE; LISBETH CERIANI; RUNI LIMARY; GENAE GIRARD; PATRICE FORTUNE; VICKY THOMASON; KATHLEEN RAKER, Plaintiffs,
09 Civ. 4515 (RWS)
ECF Case v. UNITED STATES PATENT AND TRADEMARK OFFICE; MYRIAD GENETICS; LORRIS BETZ, ROGER BOYER, JACK BRITTAIN, ARNOLD B. COMBE, RAYMOND GESTELAND, JAMES U. JENSEN, JOHN KENDALL MORRIS, THOMAS PARKS, DAVID W. PERSHING, and MICHAEL K. YOUNG, in their official capacity as Directors of the University of Utah Research Foundation, Defendants. --------------------------------------------------------------------------x PLAINTIFFS' COUNTERSTATEMENT TO THE MYRIAD DEFENDANTS' RULE 56.1 STATEMENT OF MATERIAL FACTS Pursuant to the Federal Rules of Civil Procedure and Local Civil Rule 56.1, Plaintiffs in the above-captioned action hereby respond and submit this Counterstatement to the Myriad Defendants'1 Local Rule 56.1 Statement of Material Facts, without admitting that any of Defendants' statements are material:
"Myriad Defendants" refer to defendants Myriad Genetics and the directors of the University of Utah Research Foundation, sued herein in their official capacity.
1. "DNA" stands for deoxyribonucleic acid, which is a chemical compound made up of deoxyribonucleotides linked by a phosphodiester backbone. Kay ¶¶ 14, 125; Linck ¶ 70. Plaintiffs' response: Admit except deny that DNA is solely a chemical. Klein ¶¶ 8-13; Mason Supp. 21-22. 2. A DNA molecule is composed of several chemical elements, namely Carbon, Hydrogen, Oxygen, Nitrogen, and Phosphorus. These chemical elements make up repeating units that are connected to form a strand or polymer of the DNA molecule. Kay ¶¶ 14, 125. Plaintiffs' response: Admit except deny that DNA is solely a chemical. See response to item 1. 3. DNA can exist as single strand or as double strand molecule. Kay ¶ 14. Plaintiffs' response: Admit. 4. The repeating units of DNA are known as nucleotides. The standard nucleotides in vertebrate DNA contain four different bases: Adenine, Thymine, Cytosine, and Guanine. These bases are linked together by chemical bonds via a sugar-phosphate backbone. Kay ¶¶ 14, 125. Plaintiffs' response: Admit. 5. As shorthand for convenience, scientists often denote nucleotides by the first letter of the names of their bases: "A" for Adenine; "G" for Guanine; "T" for Thymine; and "C" for Cytosine. Kay ¶¶ 14, 125. Plaintiffs' response: Admit. 6. A nucleotide sequence is a scientific notation understood in the field of human genetics as the primary structure of the DNA molecule, akin to formulae that represent chemical compounds, e.g., H2O represents 2 atoms of hydrogen and 1 atom of oxygen that form the molecule water. Kay ¶ 127; Schlessinger ¶ 19; Doll ¶ 31; Linck ¶ 45. Plaintiffs' response: If "nucleotide sequence" means the letters that represent the nucleic acid sequence, admit. If it is meant to include the nucleic acid sequence, deny. Deny that a nucleotide sequence is akin to water. Mason Supp. ¶ 21; Klein ¶ 12.
7. A nucleotide sequence or a DNA sequence is a description of the linear order of nucleic acids that make up the polynucleotide; it is not itself a chemical compound. Kay ¶ 10; Doll ¶ 31. Plaintiffs' response: Neither declaration supports the statement. If "sequence" in this sentence is meant to be defined solely by the letters that represent the nucleic acid sequence, admit. If "sequence" means the nucleic acid sequence, deny. See answer to item 6. 8. DNA as it is found in the human body, i.e., native DNA, is one integral component of chromosomes. Chromosomes are complex structures that carry genes which are located in most cells of the human body. Proteins represent another integral component of chromosomes. These proteins are bound to the DNA molecules in the chromosomes and modulate the structure and function of the DNA molecules to which they are bound. Kay ¶ 131; Schlessinger ¶ 12. Plaintiffs' response: Admit. 9. Thus, native DNA is never found floating freely in cells of the body, but is packaged along with proteins to form chromosomes. Kay ¶ 131. Plaintiffs' response: Deny. Mason Supp. ¶ 18; Nussbaum ¶ 42. 10. The dynamic interaction between chromosomal proteins and native DNA in the body has a major role in establishing which genes are active and which are inactive and the level of their activity. Kay ¶ 132. Plaintiffs' response: Admit that the described interaction is one method by which genes are made active and the level of their activity. Deny that it is the only method. Nussbaum ¶¶ 173; Klein ¶ 19. 11. In addition, the chromosomal proteins mediate the interplay between the native DNA and the rest of the cell. Kay ¶ 132. Plaintiffs' response: Same response as paragraph 10. 12. Chemical modifications of the DNA molecule, e.g., methylation, can have a major impact on the function of the DNA molecule in the body. Accordingly, there are many factors in the cell, so-called epigenetic factors, which can influence native DNA and consequently the presentation of a trait. Kay ¶ 132. Plaintiffs' response: Admit that methylation can have an effect on some functions in the body. Deny that it has any effect on the function of providing information on the nucleic acid
sequence. Further, note that DNA occurs in the body without being subject to methylation. Same response as paragraph 10; Mason Supp. ¶ 22. 13. The body does not have a mechanism for isolating genes. Kay ¶ 143. Schlessinger ¶ 11; Linck ¶ 52. Plaintiffs' response: Admit subject to the response to paragraph 9. 14. An "isolated DNA" or "isolated DNA molecule" is DNA that has been extracted from the cell and excised from the chromosome, or chemically synthesized. Kay ¶¶ 17, 137. Plaintiffs' response: This fact is purely a definition of the term "isolated." Deny that it is consistent with the definition in the patents. See the patents.2 Deny "synthesized" DNA, such as primers made using chemical reactions or biochemical procedures, are isolated from "native" DNA. Nussbaum ¶ 13. 15. An isolated DNA is made by the hand of the scientist. Kay ¶¶ 17, 137. Plaintiffs' response: Deny. Sulston ¶¶ 10-27; Leonard ¶ 15; Mason ¶¶ 23, 33; Love ¶ 10; Chung ¶¶ 10, 25; Ostrer ¶ 14; Ledbetter ¶ 27; Mason Supp. ¶ 18-23; Nussbaum ¶¶ 17-42; Klein ¶¶ 26-37. 16. To isolate DNA molecules from the body, the entire genome must be extracted from tissues or cells of the body and the chromosomal proteins must be removed. Kay ¶ 133. Plaintiffs' response: This fact is purely a definition of the term "isolated." Deny that it is consistent with the definition in the patents. See the patents. Admit that in order to sequence DNA from the body, these steps must be taken. 17. To isolate a specific gene of interest, relevant DNA fragments must be excised from the genome. Kay ¶ 133. Plaintiffs' response: This fact is purely a definition of the term "isolated." Deny that it is consistent with the definition in the patents. See the patents. Definition appears to be
All references herein to "the patents" refer to the patents challenged in this action: U.S. Patent No. 5,747,282, U.S. Patent No. 5,837,492, U.S. Patent No. 5,693,473, U.S. Patent No. 5,709,999, U.S. Patent No. 5,710,001, U.S. Patent No. 5,753,441, and U.S. Patent No. 6,033,857.
contradictory to Fact in paragraph 16. To the extent this fact is simply saying "to have a gene by itself, you must separate it from others," it is tautological. 18. The dynamic chemical, physical, and functional interaction between DNA and chromosomal proteins is therefore eliminated from an isolated DNA molecule. Kay ¶ 133. Plaintiffs' response: This fact is purely a definition of the term "isolated." Deny that it is consistent with the definition in the patents. See the patents. Definition appears to be contradictory to Fact in paragraph 17. To the extent this fact is simply saying "a gene separated from chromosomal proteins will not interact with chromosomal proteins," it is tautological. 19. An isolated complementary DNA, or "cDNA" molecule is an artificial construct that does not exist in the body and is structurally and functionally different from both native DNA and RNA (ribonucleic acid). Kay ¶¶ 148, 164; Linck ¶ 48. Plaintiffs' response: Deny. Mason Supp. ¶¶ 18-21; Nussbaum ¶¶ 41-42. 20. In the cell, RNA is generated by a process called transcription. The RNA transcribed from one gene is processed into one or more messenger RNAs ("mRNAs") through a process called alternative splicing. Thus a single gene may give rise to various different mRNA molecules, which in turn give rise to various different proteins through a process called translation. Kay ¶¶ 149-152; Schlessinger ¶¶ 13-14. Plaintiffs' response: Admit. 21. A cDNA molecule is synthesized from a mRNA in a reaction catalyzed by a protein known as reverse transcriptase. cDNA received its name because each base in the cDNA can bind to a base in the mRNA from which the cDNA is synthesized. In other words, it is "complementary" to the mRNA from which it is synthesized. Kay ¶ 161. Plaintiffs' response: Admit, except deny to the extent that "synthesized" excludes things that also exist in the body. Nussbaum ¶ 42; Mason Supp. ¶¶ 18-19. Also deny to the extent that "synthesized" implies that naturally-occurring products and processes are not the basis for their making. Mason ¶¶ 28-32.
22. Several steps are required to construct a cDNA, involving many molecular biology techniques. First, mature RNA is isolated from the tissues or cells of an organism. cDNA is then synthesized from the mature RNA using reverse transcriptase. Kay ¶ 165. Plaintiffs' response: Admit, except deny to the extent that "synthesized" excludes things that also exist in the body. Nussbaum ¶ 42; Mason Supp. ¶¶ 18-19. Also deny to the extent that "synthesized" implies that naturally-occurring products and processes are not the basis for their making. Mason ¶¶ 28-32. 23. In this process, the bases of the RNA serve as clamps while the chemical bonds between the nucleotides of the newly forming cDNA strand are formed. Uracil binds to and thereby acts as a clamp for Adenine, Thymine for Adenine, Guanine for Cytosine, and Cytosine for Guanine. Kay ¶ 165. Plaintiffs' response: Admit. 24. Initially, the cDNA is single stranded but the second strand can be synthesized to form a double stranded cDNA molecule. Kay ¶ 166. Plaintiffs' response: Admit. 25. The synthesis of cDNA from very long mRNA molecules, such as BRCA1 and BRCA2, often does not result in a cDNA strand that is as long as the mRNA chain. Instead, not unlike a puzzle, several cDNA fragments have to be pieced together to arrive at a composite full length cDNA. Kay ¶ 166. Plaintiffs' response: Admit that the process of reverse transcriptase sometimes does not result in a full cDNA strand as long as the BRCA1 or BRCA2 genes, but deny that the cDNA fragments are or have to be chemically pieced together. Mason Supp. ¶ 19. 26. Isolated DNA molecules are distinct from any substance found in the human body. Kay ¶ 137. Plaintiffs' response: Deny. See response to paragraphs 9 and 15.
27. Once a DNA molecule is isolated, it gains new properties which, in its native state, it did not possess. These new properties impart the isolated DNA molecules with new characteristics and new utilities. These new functions make isolated DNA molecules useful as tools for many biotechnological applications such as, for example, diagnostic assays to identify and detect potentially harmful human genetic alterations. Kay ¶¶ 134, 138; Schlessinger ¶ 28; Doll ¶¶ 27-29. Plaintiffs' response: Deny. Sulston ¶¶ 10-27; Leonard ¶ 15; Mason ¶¶ 23, 33; Love ¶ 10; Chung ¶¶ 10, 25; Ostrer ¶ 14; Ledbetter ¶ 27; Mason Supp. ¶¶ 18-23; Nussbaum ¶¶ 17-42; Klein ¶¶ 26-37. 28. Unlike native DNA, isolated DNA can be used as a probe, a diagnostic tool that a molecular biologist uses to target and bind to a particular portion of DNA, allowing it to be detectable using laboratory machinery. Native DNA cannot be used this way. Kay ¶ 138; Schlessinger ¶ 29. Plaintiffs' response: To the extent this claims that "native DNA" does not target and bind to a particular portion of DNA, denied. To the extent this claims that "isolated DNA" at full-length is generally used as a probe, denied. To the extent this claims that a fragment of DNA is sometimes used as a probe once modified with a marker, admitted. Mason Supp. ¶¶ 1415; Klein ¶ 38; Nussbaum ¶ 40. 29. Isolated DNA can also be used as another diagnostic tool, a "primer," which can be used in "sequencing" DNA, a method used by a molecular biologist to determine the primary structure of a DNA molecule. In sequencing, a primer binds to, or "hybridizes" with, a DNA target, such as a BRCA1/2 genomic DNA, or a cDNA to form a hybridization product that acts as a substrate for the enzymes used in the sequencing reaction. Kay ¶ 138; Schlessinger ¶ 30. Plaintiffs' response: Deny. Nussbaum ¶ 40; Klein ¶ 38; Mason ¶¶ 16-17. 30. Native DNA does not have the chemical, structural, or functional properties that make isolated DNA so useful to the molecular biologist. Native DNA cannot be used as molecular tools, such as probes and primers, and cannot be used to detect mutations. Nor can it be used in sequencing reactions to determine the structure of a DNA molecule. Kay ¶ 139. Plaintiffs' response: Deny. See responses to paragraphs 28-29.
31. Extraction, excision, and purification from cellular components, or synthesizing DNA directly from its nucleotide components, is essential to be able to use the isolated DNA molecules as primers or probes. Thus, only isolated DNA molecules have the required chemical, structural and functional properties important for use as diagnostic tools and in the claimed diagnostic methods. Kay ¶ 139. Plaintiffs' response: See response to paragraphs 28-29. 32. cDNA, like other isolated DNA molecules that are extracted, excised or synthesized, can be a useful tool for researchers as primers and probes in biotechnological and diagnostic applications. Kay ¶ 162. Plaintiffs' response: See response to paragraphs 28-29. 33. Moreover, when a scientist wants to express a specific protein in a cell that does not normally express that protein to learn more about the protein, the scientist can transfer the cDNA that codes for the protein to a recipient cell. If the cDNA is operatively linked to a promoter that initiates transcription from the cDNA, the recipient cell will then express the protein of interest. Kay ¶ 163. Plaintiffs' response: Admit. 34. cDNA is structurally different from native DNA in human cells. Kay ¶ 168. Plaintiffs' response: Deny that cDNA is not found in human cells. Deny that cDNA is structurally different except admit that cDNA does not include introns and has a polyA tail. Mason ¶¶ 28-29; Mason Supp. ¶¶ 18-21; Nussbaum ¶¶ 41-42. 35. First, cDNA made from an mRNA does not contain introns in contrast to native human genes, which contains many intronic sequences. Second, cDNA can contain nucleotides that correspond to the poly-adenine tail of mRNA, which does not exist in native DNA. Third, because it is not associated with proteins as with native DNA and because it lacks a 5' cap, no protein can be produced from an isolated cDNA molecule without introduction of regulatory structures. Fourth, the sugar-phosphate backbone of native DNA is usually chemically modified, e.g., by methylation. In contrast, the sugar-phosphate backbone of cDNA is not modified. Finally, as discussed above, isolated cDNA can serve as a probe, as a target for a probe, and as a template for a polymerase chain reaction ("PCR"), all of which native mRNA cannot do. Kay ¶ 168. Plaintiffs' response: Admit the first sentence. Admit the second and third sentences only insofar as they describe "can" occur rather than what does occur or what must occur. Admit the fourth and fifth sentences only insofar as they describe "usually." Deny the "Finally..."
sentence to the extent it suggests that DNA can't be used as a template or that full-length cDNA can be used as described. See response to paragraphs 28-29; Klein ¶ 13. 36. cDNA is also functionally different from native DNA. Kay ¶ 169. Plaintiffs' response: Deny. See response to paragraph 15. 37. First, native DNA contains regulatory regions. These regulatory regions are not present in cDNA because they are not present in the mRNA from which the cDNA was synthesized. Second, because cDNA does not contain intronic sequences, mRNA can be transcribed from cDNA without the need for splicing. Third, introducing a cDNA alone into a cell does not give rise to protein production from that cDNA. Fourth, native DNA and chromosomal proteins form a functional unit; isolated or synthetic cDNA, however, is not associated with chromosomal protein and can thus be used as a molecular tool in various biotechnological applications. Kay ¶ 169. Plaintiffs' response: Admit the first sentence. Deny all following sentences. Nussbaum ¶¶ 41-42; Mason ¶¶ 18-21. 38. As with native DNA, cDNA is structurally different from RNA, both pre-mRNA and mature mRNA. Kay ¶ 170. Plaintiffs' response: Admit subject to response to paragraph 34. 39. First, the set of bases in DNA is different from the set of bases in RNA. While the four bases in DNA are Adenine, Cytosine, Guanine, and Thymine, the four bases in RNA are Uracil, Adenine, Cytosine, and Guanine. Second, the sugar-phosphate backbone in DNA is chemically different from the sugar-phosphate backbone of RNA. This difference in structure allows DNA to form the famous double helix. Kay ¶ 170. Plaintiffs' response: Admit. 40. cDNA is also functionally different from mRNA. Kay ¶ 171. Plaintiffs' response: See response to paragraphs 34-39.
41. First, cDNA is a much more stable molecule than mRNA. Second, protein can be translated directly from mRNA, whereas protein cannot be directly translated from cDNA, but requires the additional step of RNA transcription. Third, in the body, tens of thousands different mRNA molecules are present. Synthesized cDNA, on the other hand, is generated in the laboratory, commonly as a homogenous population of molecules of the same kind to study the properties and functions of a specific gene of interest. Kay ¶ 171. Plaintiffs' response: Admit sentences 1-3. Deny sentence 4. Klein ¶ 35; Mason Supp. ¶¶ 18-21; Nussbaum ¶¶ 41-42. 42. The physical form of a DNA molecule can significantly impact its function and the information it can yield. Kay ¶ 141. Plaintiffs' response. Term "physical form" is ambiguous. If this means the shape of the DNA, or if it means "isolated" rather than "native," deny. If it means CATG conveys different information than TATG, it is a tautology. See response to paragraph 15; Mason Supp. ¶ 22; Klein ¶¶ 12-29. 43. The usefulness of isolated BRCA1/2 DNA molecules is based on their ability to target and interact with native DNA, or isolated BRCA1/2 DNA molecules themselves, which is a function of their own individual structure and chemistry. Kay ¶ 138. Plaintiffs' response: Deny. See response to paragraph 27. 44. Only isolated DNA molecules have the required chemical, structural and functional properties important for use as diagnostic tools. Kay ¶¶ 139, 174. Plaintiffs' response: Deny. See response to paragraph 15. 45. A DNA sequence cannot be obtained by "looking" at genes. One cannot detect or determine the sequence of a human subject's genes by mere inspection. Detection of a gene marker requires breaking open the cells of a tissue sample, and extracting and excising the native DNA. Kay ¶ 187. Plaintiffs' response: Deny. Klein ¶¶ 12-37.
46. The gene, mRNA and allele are in the body and must be obtained from a patient's tissue sample in order to be sequenced. The cells of the tissue sample must be broken open and a sample of DNA or RNA or allele extracted from the cells. cDNA can be synthesized using mRNA obtained from the patient sample. Various types of patient samples can be used, for example, a blood, tumor tissue, or non-tumor tissue samples. Kay ¶ 186. Plaintiffs' response: Admit except for the "a sample of" limitation Deny that sequencing requires that a "sample of" DNA be obtained. Klein ¶¶ 12-37. 47. The DNA has to be isolated from these samples and put through sequencing reactions in order to obtain the sequence. This is transformative--the blood sample no longer resembles blood, and the patient's tissue no longer resembles the tissue. Kay ¶ 186. Plaintiffs' response: Deny. See response to paragraph 27. 48. To determine a DNA sequence of a patient for diagnostic purposes, a biological sample, such as a blood sample, from the patient must be processed. Native DNA or mRNA must be purified from the patient sample. Kay ¶ 178. Plaintiffs' response: It is not possible to admit or deny this item without a definition of "purified" and "processed." In the prior three paragraphs, defendants appear to define "isolated" to mean taking DNA out of the cell and cutting it to a specific length. It is, therefore, not clear what the use of "purified" or "processed" means in this context. To the extent purified and processed is synonymous with isolated, plaintiffs deny. See responses to paragraphs 14 and 46. 49. The purification of native DNA of the entire genome, however, does not result in the purification of a single gene. Given that the human genome is over three billion nucleotides long, this initial purification step is still a long way from obtaining the sequence of a specific gene. To put things in perspective, the size of the BRCA1 cDNA relates to the size of the entire genome approximately as a grain of sand to the height of the observation floor of the Empire State Building. Kay ¶178. Plaintiffs' response: See response to paragraph 48. 50. Similarly, purification of mRNA from a patient sample yields a mixture of thousands or tens of thousands of different mRNA molecules. Even if cDNA is synthesized from this pool of mRNA molecules, the resulting cDNA molecules are similarly a mixture of thousands or tens of thousands of different cDNAs. Kay ¶ 179. Plaintiffs' response: See response to paragraph 48.
51. To initiate the sequencing reaction at the desired location of a target in the sample, a primer is used. A primer is an artificial DNA fragment, usually between 15 and 30 nucleotides long, that binds specifically to the target nucleotide. The nucleotide sequence of the primer is complementary to the sequence of the target such that the bases of the primer and the bases of the target bind to each other. Kay ¶¶ 177, 183. Plaintiffs' response: Deny. A primer need not be used. To the extent this is defining what a primer does, admit. Klein ¶¶ 12-38; Nussbaum ¶¶ 12-23. 52. Thus, to sequence a particular target within a sample, at least part of the target sequence must be known to design a suitable primer. The initial sequencing of a target sequence requires ingenuity far beyond the mere application of routine laboratory techniques and usually involves a significant amount of trial and error. Kay ¶ 179. Plaintiffs' response: See response to paragraph 51. 53. Target-sequence specific primers can also be used to initiate polymerase chain reaction ("PCR"), a technique that can be employed to synthesize and isolate specific target DNA fragments for sequencing. For example, PCR can be used to synthesize a fragment of genomic DNA. The resulting fragment can then be sequenced. However, to do so, at least part of the sequence of the target DNA molecule must be known so that the target specific primer can be designed. Thus, the use of PCR requires knowledge of at least part of the sequence of the target DNA to design these specific primers. Kay ¶ 184. Plaintiffs' response: See response to paragraph 51. 54. After diagnostic sequencing, the patient's sample, such as blood or tissue, is no longer blood or tissue but has been processed to obtain DNA. The DNA has then been subjected to a sequencing reaction. At the end, instead of blood or tissue, the clinician has the chemical structure of a small portion of the patient's DNA. Kay ¶ 185. Plaintiffs' response: Deny. See response to paragraph 15. 55. For example, using a set of molecular tools, such as a diagnostic probe or a primer that can specifically bind to a BRCA1/2 DNA molecule in a tissue sample, the patient's native DNA is analyzed to determine if the structural composition is the same or different from the normal native gene. These molecular diagnostic tools were designed based on their ability to bind to and form a stable chemical structure with a target gene. Kay ¶ 187. Plaintiffs' response: Admit that the patient's native DNA (which Myriad defines as not "isolated") is compared to the normal native (non-"isolated") gene. See response to paragraph 51.
56. To detect a mutation in the BRCA1 and BRCA2 genes, the first step typically is to obtain a sufficient amount of the genomic DNA corresponding to the BRCA1 and BRCA2 genes from a patient's tissue sample (e.g., blood). This step is typically done by enzymatic synthesis to connect different nucleotide molecules into a DNA chain using a genomic DNA molecule from the patient sample as a template. Critchfield ¶ 40. Plaintiffs' response: Admit first sentence. Deny second sentence. Klein ¶¶ 12-38; Nussbaum ¶¶ 12-23. 57. To obtain a sufficient quantity of the genomic DNA, the enzymatic synthesis is performed by PCR (polymerase chain reaction) to duplicate the DNA molecule exponentially. Critchfield ¶ 40. Plaintiffs' response: Admit. 58. However, there is a limit in the size of the genomic DNA fragment that can be made by PCR (about several hundred base pairs). The BRCA1 and BRCA2 genes are large in size each being over 70,000 base pairs long, and can not be amplified or duplicated into a single DNA fragment. Critchfield ¶ 40. Plaintiffs' response: Admit that there is a limit. Deny that the patents describe the BRCA genes as each over 70,000 base pairs. See, e.g., patent `282, Fig. 10A (listing under 25,000 base pairs with introns included), SEQ. ID NO. 1 (defining claim 2 as 5914 base pairs without introns included). See also contradictory fact in paragraph 59. 59. Under the current state of the art, the only practical way to obtain a sufficient amount of BRCA1 or BRCA2 genomic DNA for mutation detection purpose is to PCR amplify the genomic DNA in segments. Typically, each coding exon (an exon that codes for part of the protein) of the BRCA1 and BRCA2 genes, including a small adjacent portion of the flanking introns, is separately amplified by PCR into one or more amplified DNA fragments, also called "amplicons." The BRCA1 and BRCA2 genes have a total of 48 coding exons containing over 15,700 nucleotide base pairs. More than 50 amplicons are typically produced, and each is subsequently interrogated for the presence or absence of mutations. Critchfield ¶ 40. Plaintiffs' response: Admit.
Dated: January 20, 2010
Respectfully submitted, /s/ Christopher A. Hansen Christopher A. Hansen Aden Fine American Civil Liberties Union Foundation 125 Broad Street 18th floor New York, NY 10004 212-549-2606 firstname.lastname@example.org email@example.com Sandra S. Park Lenora M. Lapidus Women's Rights Project American Civil Liberties Union Foundation 125 Broad Street 18th floor New York, NY 10004 212-519-7871 firstname.lastname@example.org email@example.com Daniel B. Ravicher Sabrina Y. Hassan Public Patent Foundation (PUBPAT) Benjamin N. Cardozo School of Law 55 Fifth Avenue, Suite 928 New York, NY 10003 (212) 790-0442 firstname.lastname@example.org email@example.com Attorneys for Plaintiffs
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