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

Filing 578

DECLARATION of Harvey F. Lodish, Ph.D. in Support of Opposition to Roche's Motion for Summary Judgment of Invalidity for Double Patenting Over Claim 10 of the '016 Patent by Amgen Inc.. (Attachments: #1 Part 2 of Declaration of Lodish#2 Errata Ex. A#3 Exhibit Ex. B#4 Exhibit C#5 Exhibit Ex. D#6 Exhibit Ex. E-I#7 Exhibit Ex. E-II#8 Exhibit Ex. F#9 Exhibit Ex. G#10 Exhibit Ex. H#11 Exhibit Ex. I#12 Exhibit Ex. J#13 Exhibit Ex. K#14 Errata Ex. L#15 Errata Ex. M#16 Exhibit Ex. N#17 Exhibit Ex. O#18 Exhibit Ex. P#19 Exhibit Ex. Q#20 Exhibit Ex. R#21 Exhibit Ex. S-1#22 Exhibit Ex. S-2#23 Exhibit Ex. S-3#24 Exhibit Ex. T#25 Exhibit Ex. U-1#26 Exhibit Ex. U-2#27 Exhibit Ex. V#28 Errata Ex. W#29 Exhibit Ex. X#30 Exhibit Ex. Y-1#31 Exhibit Ex. Y-2#32 Exhibit Ex. Z)(Rich, Patricia)

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DECLARATION OF HARVEY F . LODISH, Ph .D . IN SUPPORT OF AMGEN INC .'S OPPOSITION TO ROCHE'S MOTION FOR SUMMARY JUDGMENT OF INVALIDITY FOR DOUBLE PATENTING OVER CLAIM 10 OF THE `016 PATENT PART 2

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My opinion would be the same if the relevant date of analysis were prior to November 30, 1984 .
II

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12 Amgen Inc . v . Chugai Pharm . Co . Ltd., 13 U.S .P .Q .2d 1737, 1748 (D . Mass . 1989) .

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DNA sequences that encode human EPO, but differ from the natural EPO DNA sequences by including preferred codons for expression in prokaryotic and yeast cells ; Demonstrations of immunological, in vitro, and in vivo biological properties of EPO produced by genetically manipulated cells ; and Methods for treating anemic patients by EPO therapy . Particularly as of 1983-84, the breadth and quality of Dr . Lin's experiments and

· ·

90 .

the description of his methods and results were impressive, reflecting a series of truly breakthrough discoveries that garnered significant attention, respect, and acclaim when they were reported to the scientific community .
F. CLAIMS 3, 7-9,11-12 AND 14 OF DR . LIN'S'933 PATENT WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART IN 1983-84, EVEN IN LIGHT OF `016 CLAIM 10

91 .

The differences between `016 claim 10 and `933 claims 3, 7-9, 11-12 and 14 are

shown in the following chart : `016 Claim 0 10 . A process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid, said process comprising the following steps in sequence : (1) subjecting the fluid to ion exchange chromatographic separation at about pH 7 .0, thereby to selectively bind erythropoietin in said sample to a DEAE agarose cationic resin; (2) stabilizing materials bound to said resin against degradation by acid activated proteases through treatment with urea ; (3) selectively eluting bound materials having a pKa greater than that of erythropoietin by treatment with aqueous acid at a pH of about `933 Claims 3, 2, 3 . A non-naturally occurring erythropoietin glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin said product possessing the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells . 7 . The glycoprotein product according to claim 3, 4, 5 or 6 wherein the host cell is a non-human mammalian cell . 8 . The glycoprotein product according to claim 7 wherein the non-human mammalian cell is a CHO cell . 9 . A pharmaceutical composition comprising 39

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4 .3 . (4) selectively eluting erythropoietin by treatment with an aqueous salt at a pH of about 7 .0 ; (5) subjecting erythropoietin-containing eluent fractions to reverse phase liquid chromatographic separation involving an immobilized C4 resin, thereby to selectively bind erythropoietin in said fluid to said resin ; (6) selectively eluting bound erythropoietin from said resin with an aqueous ethanol solution of about 60 percent at a pH of about 7 .0 ; and, (7) isolating erythropoietin-containing fractions of the eluent .

an effective amount a glycoprotein product effective for erythropoietin therapy according to claim 1, 2, 3, 4, 5 or 6 and a pharmaceutically acceptable diluent, adjuvant or carrier. 11 . A method for treating a kidney dialysis patient which comprises administering a pharmaceutical composition of claim 9 in an amount effective to increase the hematocrit level of said patient . 12 . A pharmaceutical composition comprising an effective amount of a glycoprotein product effective for erythropoietin therapy according to claim 7 and a pharmaceutically acceptable diluent, adjuvant or carrier . 14 . A method for treating a kidney dialysis patient which comprises administering a pharmaceutical composition of claim 12 in an amount effective to increase the hematocrit level of said product .

92 .

The asserted claims of the `933 patent are each significantly different than `016

claim 10 because they each depend on claim 3, and thus require : (1) a particular process of production of an erythropoietin glycoprotein, that (2) has a specific in vivo biological activity . Moreover, the dependent `933 asserted claims have further limitations that are not even suggested by `016 claim 10 :

· · ·

`933 Claim 7 : additionally requires that the EPO glycoprotein be produced in a nonhuman mammalian cell . `933 Claim 8 : additionally requires that the EPO glycoprotein be produced in a CHO cell . `933 Claims 9 and 12 : additionally require that the EPO glycoprotein be part of a

pharmaceutical composition .

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"One skilled in the art in 1983 would have known that rEPO, such as claimed in claim 10 of the `016 patent, could be converted into pharmaceuticals for treatment of a kidney dialysis patient by conventional and well-known means." RSF 6. I disagree with Roche's argument. In my opinion, for the reasons explained in

94.

this declaration, each of the inventions as a whole claimed in the `933 asserted claims would not have been obvious to a person of ordinary skill in the art in 1983-84, even in light of `016 claim 10. G. CLAIM 1 OF DR. LIN'S `422 PATENT WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART IN 1983-84, EVEN IN LIGHT OF `016 CLAIM 10 The differences between `016 claim 10 and `422 claim 1 are shown in the

95.

following chart: `016 Claim 10 10. A process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid, said process comprising the following steps in sequence: (1) subjecting the fluid to ion exchange chromatographic separation at about pH 7.0, thereby to selectively bind erythropoietin in said sample to a DEAE agarose cationic resin; (2) stabilizing materials bound to said resin against degradation by acid activated proteases through treatment with urea; (3) selectively eluting bound materials having a pKa greater than that of erythropoietin by treatment with aqueous acid at a pH of about 4.3. (4) selectively eluting erythropoietin by treatment with an aqueous salt at a pH of about 7.0; (5) subjecting erythropoietin-containing eluent `422 Claim 1 1. A pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, wherein said erythropoietin is purified from mammalian cells grown in culture.

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fractions to reverse phase liquid chromatographic separation involving an immobilized C4 resin, thereby to selectively bind erythropoietin in said fluid to said resin ; (6) selectively eluting bound erythropoietin from said resin with an aqueous ethanol solution of about 60 percent at a pH of about 7 .0 ; and, (7) isolating erythropoietin-containing fractions of the eluent .

96 .

Asserted claim I of the `422 patent is significantly different from `016 claim 10

because it requires a pharmaceutical composition comprised of a "therapeutically effective amount" of "human erythropoietin ." The Court has construed to "therapeutically effective" to require certain in vivo effects . The Court has construed "human erythropoietin" to require a polypeptide having the amino acid sequence of naturally occurring human EPO, including urinary EPO . Nothing in `016 claim 10 requires a product containing the amino acid sequence of `422 claim 1, nor would anything in `016 claim 10 inform or instruct one skilled in the art what the amino acid sequence of naturally occurring EPO is or how to obtain a recombinant product that comprised it . Nothing in `016 claim 10 requires a "therapeutically effective" recombinant EPO, nor would anything in claim 10 inform or instruct one skilled in the art how to obtain such a product . 97 . Notwithstanding the significant differences between these claims, Roche contends

that claim I of the `422 patent would have been obvious to one of ordinary skill in the art in 1983 in light of `016 claim 10 . Specifically, Roche contends that :
·

"One of ordinary skill in 1983 would have understood that purified rEPO, such as claimed in claim 10 of the `016 patent, was intended for use in a pharmaceutical composition, in a therapeutically effective amount ." RSF 14 ; 43

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·

"It would be routine for one skilled in the art in 1983 to combine the rEPO with a pharmaceutically acceptable diluent, adjuvant or carrier ." RSF 14 .

98 . I disagree with Roche's argument . In my opinion, for the reasons explained in this declaration, the invention as a whole claimed in claim 1 of the `422 patent would not have been obvious to a person of ordinary skill in the art in 1983-84, even in light of `016 claim 10 .
H. CLAIM 7 OF DR . LIN'S `349 PATENT WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART IN 1983-84, EVEN IN LIGHT OF `016 CLAIM 10

99 .

The differences between `016 claim 10 and `349 claim 7 are shown in the

following chart : `016 Claim 0 10 . A process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid, said process comprising the following steps in sequence : (1) subjecting the fluid to ion exchange chromatographic separation at about pH 7 .0, thereby to selectively bind erythropoietin in said sample to a DEAE agarose cationic resin ; (2) stabilizing materials bound to said resin against degradation by acid activated proteases through treatment with urea ; (3) selectively eluting bound materials having a pKa greater than that of erythropoietin by treatment with aqueous acid at a pH of about 4 .3 . (4) selectively eluting erythropoietin by treatment with an aqueous salt at a pH of about 7 .0 ; (5) subjecting erythropoietin-containing eluent fractions to reverse phase liquid chromatographic separation involving an immobilized C4 resin, thereby to selectively `349 Claim 7 . A process for producing erythropoietin comprising the step of culturing, under suitable nutrient conditions, vertebrate cells according to claim 1, 2, 3, 4, 5, or 6 . [4 . Vertebrate cells which can be propagated in vitro which comprise transcription control DNA sequences, other than human erythropoietin transcription control sequences, for production of human erythropoietin, and which upon growth in culture are capable of producing in the medium of their growth in excess of 100 U of erythropoietin per 10 6 cells in 48 hours as determined by radioimmunoassay .]

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bind erythropoietin in said fluid to said resin ; (6) selectively eluting bound erythropoietin from said resin with an aqueous ethanol solution of about 60 percent at a pH of about 7 .0 ; and, (7) isolating erythropoietin-containing fractions of the eluent .

100 . Asserted claim 7 of the `349 patent is significantly different from `016 claim 10 because it requires : (1) a particular process of production of the erythropoietin glycoprotein requiring host cells with specific genetic structures, and (2) that the erythropoietin glycoprotein be produced to certain high levels . 101 . Notwithstanding the significant differences between these claims, Roche contends that claim 7 of the `349 patent would have been obvious to one of ordinary skill in the art in 1983 in light of `016 claim 10 . Specifically, Roche contends that :
·

"Limitations relating to the host cells, including the choice of the "specific genetically-heterogeneous strain of Chinese hamster ovary (CHO) cells, which produced EPO at a rate greater than that of other cells" and limitations relating to the host cell's ability to produce EPO at a greater rate cannot be considered patentable distinctions over the "mammalian cell culture" of claim 10 of the `016 patent ." RSF 8, "because claim 7 fails to disclose or claim any method for making its rate of production possible, and also appears indefinite, its scope must be limited to what was enabled in the `349 patent, which shares the same specification as the Lin `008 patent, which was in turn incorporated into the `016 patent ." RSF 21 . I disagree with Roche's argument. In my opinion, for the reasons explained in

·

102 .

this declaration, the invention as a whole claimed in claim 7 of the `349 patent would not have been obvious to a person of ordinary skill in the art in 1983-84, even in light of `016 claim 10 .

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I.

CLAIMS 1-2 OF DR . LIN'S `868 PATENT WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART IN 1983-84, EVEN IN LIGHT OF `016 CLAIM 10 The differences between `016 claim 10 and `868 claims 1 and 2 are shown in the

103 .

following chart : `016 Claim 0 `868 Claims 1 and 2 1 . A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of: (a) growing, under suitable nutrient conditions, mammalian host cells transformed or transfected with an isolated DNA sequence encoding human erythropoietin ; and (b) isolating said glycosylated erythropoietin polypeptide therefrom . 2 . The process according to claim 1 wherein said host cells are CHO cells .

10 . A process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid, said process comprising the following steps in sequence : (1) subjecting the fluid to ion exchange chromatographic separation at about pH 7 .0, thereby to selectively bind erythropoietin in said sample to a DEAE agarose cationic resin ; (2) stabilizing materials bound to said resin against degradation by acid activated proteases through treatment with urea; (3) selectively eluting bound materials having a pKa greater than that of erythropoietin by treatment with aqueous acid at a pH of about 4 .3 . (4) selectively eluting erythropoietin by treatment with an aqueous salt at a pH of about 7 .0 ; (5) subjecting erythropoietin-containing eluent fractions to reverse phase liquid chromatographic separation involving an immobilized C4 resin, thereby to selectively bind erythropoietin in said fluid to said resin ; (6) selectively eluting bound erythropoietin from said resin with an aqueous ethanol solution of about 60 percent at a pH of about 7 .0 ; and, (7) isolating erythropoietin-containing fractions of the eluent .

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104 . The asserted claims of the `868 patent are each significantly different from `016 claim 10 because each requires : (1) a particular process for production of the erythropoietin glycoprotein in a host cell with a specific structure, and (2) that the erythropoietin glycoprotein have a specific in vivo biological activity. Moreover, dependent claim 2 has the further limitation of production in a CHO cell that is not suggested by `016 claim 10 . 105 . Notwithstanding the significant differences between these claims, Roche contends

that each of the `868 asserted claims would have been obvious to one of ordinary skill in the art in 1983 in light of `016 claim 10. Specifically, Roche contends that :
·

"the rEPO of claim 10 of the `016 patent is a glycosylated erythropoietin polypeptide which inherently has the utility of the in vivo biological property that increases production of reticulocytes and red blood cells ." RSF 20 ; "It was routine in the art in 1983 when synthesizing recombinant proteins in mammalian cells to transform or transfect the cells with the isolated DNA sequence encoding the desired protein ." RSF 20 ; "CHO cells were also well-known to those of skill in the art in 1983 as a preferred mammalian host cell culture for recombinant procedures in which biological activity was sought ." RSF 20 . I disagree with Roche's argument. In my opinion, for the reasons explained in

·

·

106 .

this declaration, each of the inventions as a whole claimed in the `868 asserted claims would not have been obvious to a person of ordinary skill in the art in 1983-84, even in light of `016 claim 10 .
J. CLAIMS 4-9 OF DR . LIN'S `698 PATENT WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF ORDINARY SKILL IN THE ART IN 1983-84, EVEN IN LIGHT OF `016 CLAIM 10

107 .

The differences between `016 claim 10 and `698 claims 4-9 are shown in the

following chart : 47

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`016 Claim 0 10 . A process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid, said process comprising the following steps in sequence : (1) subjecting the fluid to ion exchange chromatographic separation at about pH 7 .0, thereby to selectively bind erythropoietin in said sample to a DEAE agarose cationic resin; (2) stabilizing materials bound to said resin against degradation by acid activated proteases through treatment with urea ; (3) selectively eluting bound materials having a pKa greater than that of erythropoietin by treatment with aqueous acid at a pH of about 4 .3 . (4) selectively eluting erythropoietin by treatment with an aqueous salt at a pH of about 7 .0 ; (5) subjecting erythropoietin-containing eluent fractions to reverse phase liquid chromatographic separation involving an immobilized C4 resin, thereby to selectively bind erythropoietin in said fluid to said resin ; (6) selectively eluting bound erythropoietin from said resin with an aqueous ethanol solution of about 60 percent at a pH of about 7 .0 ; and, (7) isolating erythropoietin-containing fractions of the eluent .

`698 Claims 4-9 4 . A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of : a) growing, under suitable nutrient conditions, vertebrate cells comprising promoter DNA, other than human erythropoietin promoter DNA, operatively linked to DNA encoding the mature erythropoietin amino acid sequence of FIG. 6 ; and b) isolating said glycosylated erythropoietin polypeptide expressed by said cells . 5 . The process of claim 4 wherein said promoter DNA is viral promoter DNA . 6 . A process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells comprising the steps of : a) growing, under suitable nutrient conditions, vertebrate cells comprising amplified DNA encoding the mature erythropoietin amino acid sequence of FIG . 6; and b) isolating said glycosylated erythropoietin polypeptide expressed by said cells . 7 . The process of claim 6 wherein said vertebrate cells further comprise amplified marker gene DNA . 8 . The process of claim 7 wherein said amplified marker gene DNA is Dihydrofolate reductase (DHFR) gene DNA . 9 . The process according to claims 2, 4, and 6 wherein said cells are mammalian cells .

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108 . The asserted claims of the `698 patent are each significantly different from `016 claim 10 because they each require : (1) a particular process of production of the erythropoietin glycoprotein requiring vertebrate host cells with specific genetic structures (claim 4 : an operatively linked non-EPO promoter, claim 6 : amplified EPO DNA), and (2) that the erythropoietin glycoprotein have a specific in vivo biological activity. Moreover, the dependent claims have further limitations that are not suggested by `016 claim 10 :
· · ·

`698 Claim 5 : additionally requires that the promoter DNA be viral promoter DNA . `698 Claim 7 : additionally requires that there be amplified marker DNA in the host cell . `698 Claim 8 : additionally requires that the amplified marker DNA be the DHFR gene . `698 Claim 9 : additionally requires that the host cells be mammalian host cells .

·

109 . Notwithstanding the significant differences between these claims, Roche contends that each of the `698 asserted claims would have been obvious to one of ordinary skill in the art in 1983 in light of `016 claim 10. Specifically, Roche contends that :
·

"The rEPO of claim 10 of the `016 patent is a glycosylated erythropoietin polypeptide which inherently has the in vivo biological property that increases production of reticulocytes and red blood cells." RSF 15 ; "The `suitable nutrient conditions' and `vertebrate cells' of claim 4 of the `698 patent are inherent in the `016 patent claim 10's mammalian cell culture of rEPO." RSF 15 ; "The `promoter DNA, other than human erythropoietin promoter DNA' of claim 4 was routinely used in recombinant protein synthesis in 1983 ." RSF 15 ; "`DNA encoding the mature erythropoietin amino acid sequence of FIG . 6' would be produced by the process of claim 10 of the `016 patent in the mammalian cells ." RSF 15 ;

·

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·
·

"Claim 4's step of `isolating said glycosylated erythropoietin polypeptide expressed by said cells' corresponds to step 7 of the `016 patent claim 10 ." RSF 15 ; Viral promoter DNA "was a routine part of the synthesis of recombinant proteins in 1983 ." RSF 16 ; "Amplified DNA was routinely used in recombinant protein synthesis in 1983 and one skilled in the art in 1983 would have known to use the claim 10 process of the `016 patent to produce human EPO ." RSF 17 ; "Both amplified marker gene DNA and DHFR gene DNA were routinely used techniques during synthesis of recombinant proteins in 1983 and thus would have been obvious to one skilled in the art in light of claim 10 of the `016 patent ." RSF 18 ; Mammalian cells "[are] an explicitly covered element of the `016 patent claim 10 ." RSF 19 . I disagree with Roche's argument. In my opinion, for the reasons explained in

·

·

·

110 .

this declaration, each of the inventions as a whole claimed in the `698 asserted claims would not have been obvious to a person of ordinary skill in the art in 1983-84, even in light of `016 claim 10 . II. M Y OPINIONS IN THE INRE COL UAIBI1I UNIYERSITYPJITENT LITIGf1TIONCASE ARE CONSISTENT WITH MY OPINIONS IN THIS CASE 111 . The patents involved in the In Re Columbia University Patent Litigation case

(Columbia case) contain claims that broadly encompass various aspects of cotransformation and coamplification and involve DNAs that encode proteinaceous material and glycoproteins . 112 . One of my opinions in the Columbia case was that later claims that recite

glycoproteins generally are obvious in view of the recital of particular glycoproteins in the earlier claims . A glycoprotein is simply a protein that has a least one sugar residue attached to it . As I explained in my Rebuttal Expert Report in the Columbia case none of the later claims requires that the glycoprotein be functional or therapeutically useful following administration to humans 50

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or animals . None of the later claims requires that the protein be glycosylated in the same manner as in the donor species or that the cells reproduce any specific pattern of glycosylation . None requires any particular post-translational modification . None requires that the protein be "properly" modified following translation . All that is required is that the stated protein be a glycoprotein, i .e ., that it have at least one sugar attached to it . 13 113 . Roche contends that my opinions in the Columbia case support their argument

that Lin's claimed inventions would have been obvious as of 1983 . This is not true . In my Columbia report, I surveyed the state of the art as it related to certain subject matter at issue in the Columbia case . I did not attempt to survey or characterize the complete state of the art, nor did I address the complex choices and uncertainties that would have confronted one, such as Lin, who wished to produce a specific human glycoprotein having a specific in vivo biological function . 114 . In Columbia, the issue was whether previously issued claims to production of

proteins in CHO cells rendered obvious subsequently issued claims to production of glycoproteins in CHO cells . In Columbia, the only difference between the earlier claims and the later claims was a distinction between proteins and glycoproteins, without any regard to whether the glycoproteins needed to be functional . Mammalian cells, such as CHO cells, were known to glycosylate certain proteins they produced . To one skilled in the art at the time, the production of a protein in CHO cells would have implied the production of a glycosylated protein, and thus a later claim to production of glycoproteins in CHO cells added nothing significantly different than the earlier claim to production of proteins in CHO cells . Since the later claim to glycoproteins did not specify a particular carbohydrate structure, or any functional difference
13

See Exhibit Z, Rebuttal Expert Report of Harvey F . Lodish, Ph .D . (Sept. 17, 2004) at ¶ 17 . 51

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between the earlier claimed proteins and the later claimed glycoproteins to distinguish themselves from the earlier protein claims, there was no patentable distinction between the earlier protein claim and the later glycoprotein claim . In other words, a skilled artisan would reasonably have predicted that the expression of a protein in CHO cells would produce a protein having at least some glycosylation, and that prediction would likely have proved to be true once the experiment was actually performed . 115 . Here, however, the issue is very different . CHO cells do not normally produce erythropoietin, and before Lin's inventions, it was not known whether CHO cells could and would produce an erythropoietin glycoprotein that would perform the specific in vivo biological functions of human EPO : stimulating the production of red blood cells . Indeed, as detailed above and in my expert reports, there were then many reasons for skilled artisans to doubt whether recombinant CHO cells growing in culture could produce a glycoprotein product that performed the in vivo function of human EPO . The fact that a cell type, such as CHO, can glycosylate a protein it produces, does not mean that the glycosylated protein it produces will have the specific glycosylation and other post translational modifications that EPO requires in order to perform its specific biological function in vivo. Before Lin's inventions, in 1983-84, a skilled artisan would not have reasonably expected that the expression of an EPO protein in CHO cells grown in culture would successfully produce a glycoprotein that performed the biological function of human EPO in vivo . Until the experiment was actually performed, and empirical proof obtained to show that the product produced and isolated from CHO cells grown in culture actually performed the biological function of EPO in vivo, the most that a skilled artisan would have said at the time was they hoped it would do so .

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116. Roche contends that portions of my expert report in the Columbia case confirm that the following techniques used in the field were obvious and well known :
· · · · ·

Transformation of mammalian cells with exogenous DNA The use of CHO cells for producing recombinant proteins The amplification of genes in mammalian cell cultures The use of dihydrofolate reductase (DHFR) The use of viral promoters The fact that various techniques were known and practiced in the art hardly means

117 .

that Lin's particular combination of techniques to solve several long-standing and highly challenging problems that others repeatedly tried but failed to solve would have been obvious . The notion is akin to the argument that a Monet painting would have been obvious because others before Monet had used paint brushes, paint, and canvas to paint water lilies . It is true that workers of ordinary skill in the art had various types of cultured cells that could be used as host cells in transformation experiments and that CHO cells were among the different cell types that could be used as host cells for DNA transformation and recombinant protein production . It was also known that amplified genes could be selected by exposing cells to selection pressure and that the dihydrofolate reductase (DHFR) gene was one of several approaches that could have been used as an amplifiable selectable phenotype . Exogenous promoters, including viral promoters, were known to function in many types of cultured mammalian cells . My opinion that these techniques could be used to express recombinant proteins generally is consistent with my opinions in this case . 118 . The fact that various types of cultured cells could be used as host cells in

transformation experiments does not eliminate the very important difference between cells

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transformed or transfected with an isolated DNA sequence encoding human erythropoietin and claim 10 of the `016 patent for a process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid . 119 . Similarly, the fact that CHO cells could be used as host cells for DNA transformation and recombinant protein production does not eliminate the very important difference between the use of CHO cells transformed with a DNA encoding human erythropoietin in a process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells, and claim 10 of the `016 patent for a process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid . 120 . The fact that amplified genes could be selected by exposing cells to selection

pressure does not eliminate the important difference between using amplified DNA encoding human EPO in a process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells and claim 10 of the `016 patent for a process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid . 121 . The fact that the dihydrofolate reductase (DHFR) gene could have been used as an amplifiable selectable phenotype does not eliminate the important distinction between using the DHFR gene in a process for the production of a glycosylated erythropoietin polypeptide having the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells and claim 10 of the `016 patent for a process for the efficient recovery of recombinant erythropoietin from a mammalian cell culture supernatant fluid .

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HARVEY F . LODISH, PH .D .

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