Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

Filing 744

DECLARATION re #743 Memorandum in Opposition to Motion, #741 MOTION to Strike , In the Alternative, Untimely Expert Testimony of Ralph A. Bradshaw Regarding Amgen's Motion for Summary Judgment of No Obviousness-Type Double Patenting (by Timothy M. Murphy) by F. Hoffmann-LaRoche LTD, Roche Diagnostics GmbH, Hoffmann LaRoche Inc.. (Attachments: #1 Exhibit A#2 Exhibit B#3 Exhibit C#4 Exhibit D#5 Exhibit E#6 Exhibit F#7 Exhibit G#8 Exhibit H)(Toms, Keith)

Amgen Inc. v. F. Hoffmann-LaRoche LTD et al

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EXHIBIT E

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UNITED STATES DISTRICT COURT DISTRICT OF MASSACHUSETTS AMGEN, INC., Plaintiff, v. Civil Action No. 05-CV-12237 WGY F. HOFFMANN-LA ROCHE, LTD., ROCHE DIAGNOSTICS GMBH, and HOFFMANN-LA ROCHE, INC. Defendants.

EXPERT REPORT OF DR. LOWE I, JOHN LOWE, M.D., declare as follows: I offer this expert report on whether the claims asserted against Roche from certain of Amgen's United States Patents, as described below, are invalid for obviousness and lack of novelty. I. QUALIFICATIONS 1. I am currently the Professor and Chair of the Department of Pathology at Case

Western Reserve University School of Medicine in Cleveland, Ohio. I have held this position since March 1, 2005. Prior to March 1, 2005, I was a Professor of Pathology at the University of Michigan Medical School, and was an Investigator of the Howard Hughes Medical Institute. I held the medical school faculty position at the University of Michigan and my position with the Howard Hughes Medical Institute since October 1, 1986. In my prior position at the University of Michigan, I spent approximately 80% of my time and effort in scientific research activities. In

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my current position, I spend approximately 40% of my time and effort in scientific research activities. 2. My past and current scientific research has focused on understanding how a

protein modification termed glycosylation contributes to the function of several specific proteins of relevance to the mammalian immune system. These proteins include: (1) the Notch family of cell surface receptors; (2) the proteins that bind to Notch proteins (Notch ligands); (3) the selectins, which are three members of a family of proteins that mediate adhesion of white blood cells to the inside of the blood vessel; and (4) selectin ligands. My role in this research continues to consist of formulating hypotheses, designing experiments, supervising the completion of these experiments by laboratory personnel comprised of PhD students, research technicians, and junior faculty members, interpreting the data forthcoming from these experiments, and helping to compose the manuscripts that report these data and their conclusions. 3. In addition to my laboratory research responsibilities, I currently administer the

Pathology Department at the Case Western Reserve School of Medicine and the University Hospitals of Cleveland. This Department has as its missions the provision of clinical laboratory and surgical pathology services to the physicians and patients at University Hospitals of Cleveland, the teaching of medical students, PhD students, and physicians in training at the Case Medical Center, and basic and applied research in biomedicine. 4. I am the sole author of four issued United States patents and two issued foreign

patents, and a coauthor of five issued United States patents. These patents include claims for novel methods for molecular cloning of genes and cDNAs encoding mammalian proteins that control glycosylation, for DNA and protein sequences derived from such cloning activities, or for the expression of a soluble recombinant molecule whose state of glycosylation is essential to

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does not provide any patentable distinction over the DNA and host cell claims 2, 4, 6, 7, 25 and 27 of the `008 patent. As described above, the prior art described numerous examples of promoters and various expression vectors including such promoters where such promoters were operably linked to drive expression of exogenous genes, and use of viral promoters, such as promoters from the SV40 virus. It would have been obvious to one of skill in using either the claimed DNA or host cells expressing such DNA to use such promoters to express DNA encoding human erythropoietin in a mammalian or other vertebrate cell, such as a COS cell or CHO cell. 184. Moreover, the use of cells comprising amplified marker DNA as recited by `698

patent claim 7, and specifically, amplified maker DNA corresponding to the DHFR gene, does not provide any patentable distinction over the DNA and host cell claims 2, 4, 6, 7, 25 and 27 of the `008 patent. As described above, prior to October 1983, the prior art described numerous examples of using amplification for transient and for stable expression of human glycoproteins in host cells such as COS cells or CHO cells, and expression vectors encoding various marker genes such as the DHFR gene for use in such methods. It would have been obvious to use such expression vectors and amplification methods to express human erythropoietin in such host cells, resulting in host cells comprising amplified marker DNA, including amplified DHFR marker gene DNA. C. 185. Claim 7 of the `349 Patent is not Patentably Distinct from Claims 2, 4, 6, 7 and 25 of the `008 Patent Dependent claim 7 of the `349 patent is directed to "a process for producing

erythropoietin" comprising culturing, "under suitable nutrient conditions" vertebrate cells described by claims 1, 2, 3, 4, 5 or 6. These claims specify that the cells can be propagated in vitro and are capable of producing human erythropoietin in excess of 100, 500 or 1000 U per 10 6 91

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cells in 48 hours. Claim 7 however does not require a specific rate of EPO production to be achieved when using these cells in the process. 186. Claims 25 and 27 of the `008 patent are directed to a recombinant mammalian

host cell, transformed in such a manner as to allow the host cell to express an erythropoietin with the "biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells." In my opinion, there is no patentable distinction between the host cell claims 25 or 27 of the `008 patent, and the process recited by `349 patent claim 7 of producing erythropoietin by culturing, "under suitable nutrient conditions" vertebrate cells capable of producing human erythropoietin in excess of 100, 500 or 1000 U per 106 cells in 48 hours. 187. As described above, prior to October 1983, mammalian cell lines such as COS

cells and CHO cells had been widely used for recombinant expression. Conditions for culturing such cells were well described and routine. Also, as described above, it would have been obvious to express a human glycoprotein, including human EPO by expressing it in mammalian host cells such as COS cells or CHO cells. As further described above, prior to October 1983, the prior art described numerous examples of using amplification to achieve high level transient and stable expression of human glycoproteins in host cells such as COS cells or CHO cells, and expression vectors for use in such methods. For example, the Goeddel `075 patent describes use of amplification to generate recombinant host cells capable of expressing tPA in amounts of 28 to 98 g per 106 cells/48 hours. (`075 patent at col. 27, table 3). 188. Based on my review, the `349 patent does not define the standard against which

the radioimmunoassay units recited in the `349 patent claims are to be defined, therefore leaving this term indefinite. The first mention of units however refers to erythropoietin with a specific activity of 70,400 units/mg of protein. `349 patent, col. 7. Assuming production of

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erythropoietin with this specific activity, it would have been obvious to use known expression vectors and amplification methods to generate recombinant host cells capable of expressing in culture erythropoietin in the range of 100-1000 units (approximately 1.4 to 14 g) per 106

cells/48 hours, as recited by `349 patent claim 7. (If one assumes a higher specific activity, the required level of protein expression would be correspondingly less). In particular, it would therefore have been obvious to one of skill to use a mammalian host cell as recited by `008 claim 25, or specifically the CHO host cell recited by `008 patent claim 27, transformed with an appropriate expression vector to allow one to generate a host cell capable of expressing human EPO at levels recited by `349 claim 7. 189. Similarly, in my opinion there is no patentable distinction between claim 2 of the

`008 patent to a DNA sequence "consisting essentially of a DNA sequence encoding human erythropoietin, and the process recited by `349 patent claim 7 for producing a human erythropoietin. Having a DNA sequence encoding human erythropoietin, as discussed above, it would have been obvious to one of skill to choose a mammalian host cell such as a CHO cell to express the human EPO protein encoded by such a DNA sequence, to use known expression vectors and amplification techniques to generate cells capable expressing human EPO at levels recited by the `349 claim 7, and to culture such cells under suitable nutrient conditions in order to produce human EPO as recited by `349 patent claim 7. Moreover, for the same reasons, there is no patentable distinction between claims 4 or 6 of the `008 patent to recombinant host cells, in particular host cells transformed with the DNA sequence encoding human erythropoietin of `008 claim 2 and the claimed process as recited by `349 patent claim 7.

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face of these documents. For the purpose of brevity, in this report I may not repeat or discuss the dates on the face of each article, patent, and document cited to herein. 246. I reserve the right to rely upon other materials generated in the further discovery

proceedings or presented at trial. In connection with my testimony, I may also use certain graphic and/or demonstrative materials to illustrate my testimony at trial, including those materials listed at Exhibit C, and perhaps other demonstratives and graphics that have not yet been prepared and those based on documents identified in this report. I assume copies of these exhibits will be provided to Amgen as required. I reserve the right to rely upon testimony or other materials generated in further discovery proceedings or presented at trial. 247. proceeding. In the last four years I have not testified at any trial, deposition or court

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