In Re Kubin

   United States Court of Appeals for the Federal Circuit


                                         2008-1184
                                  (Serial No. 09/667,859)




                 IN RE MAREK Z. KUBIN and RAYMOND G. GOODWIN



       Barbara R. Rudolph, Finnegan, Henderson, Farabow, Garrett & Dunner, L.L.P., of
Washington, DC, argued for appellants. With her on the brief were Herbert H. Mintz and
Bart A. Gerstenblith. Of counsel was Stuart L. Watt, Wendy A. Whiteford and Gail A. Katz,
Amgen Inc., of Thousand Oaks, California, and Kathleen Fowler, of Seattle, Washington.

        Janet A. Gongola, Associate Solicitor, Office of the Solicitor, United States Patent
and Trademark Office, of Arlington, Virginia, argued for the Director of the United States
Patent and Trademark Office. With her on the brief were William G. Jenks, Mary L. Kelly,
and Stephen Walsh, Associate Solicitors. Of counsel was Raymond T. Chen, Associate
Solicitor.

       Rouget F. Henschel, Foley & Lardner LLP, of Washington, DC, for amicus curiae
Biotechnology Industry Organization. With him on the brief were Stephen B. Maebius and
Philip G. Kiko. Of counsel was Hans Sauer, Biotechnology Industry Organization, of
Washington, DC, and Brian P. Barrett, Eli Lilly and Company, of Indianapolis, Indiana.

      Matthew I. Kreeger, Morrison & Foerster LLP, of San Francisco, California, for
amicus curiae Novartis Vaccines and Diagnostics, Inc. Of counsel on the brief was Beth S.
Brinkmann, of Washington, DC.

       Jeffrey P. Kushan, Sidley Austin LLP, of Washington, DC, for amici curiae
Glaxosmithkline, et al. With him on the brief were Paul J. Zegger, Jon P. Santamauro, and
Eric M. Solovy.

         James J. Kelley, Eli Lilly and Company, of Indianapolis, Indiana, for amicus curiae
Eli Lilly and Company. With him on the brief were MaryAnn Wiskerchen, Gregory A. Cox,
Steven P. Caltrider and Robert A. Armitage.

Appealed from: United States Patent and Trademark Office
               Board of Patent Appeals and Interferences
United States Court of Appeals for the Federal Circuit

                                        2008-1184
                                 (Serial No. 09/667,859)

                IN RE MAREK Z. KUBIN and RAYMOND G. GOODWIN



Appeal from the United States Patent and Trademark Office, Board of Patent Appeals
and Interferences.

                           ___________________________

                               DECIDED: April 3, 2009
                           ___________________________



Before RADER, FRIEDMAN, and LINN, Circuit Judges.

RADER, Circuit Judge.

       Marek Kubin and Raymond Goodwin (“appellants”) appeal from a decision of the

Board of Patent Appeals and Interferences (the “Board”) rejecting the claims of U.S.

Patent Application Serial No. 09/667,859 (“’859 Application”) as obvious under 35

U.S.C. § 103(a) and invalid under 35 U.S.C. § 112 ¶ 1 for lack of written description. Ex

parte Kubin, No. 2007-0819 (B.P.A.I. May 31, 2007) (“Board Decision”). Because the

Board correctly determined that appellants’ claims are unpatentably obvious, this court

affirms.

                                            I.

       This case presents a claim to a classic biotechnology invention – the isolation

and sequencing of a human gene that encodes a particular domain of a protein. This

court provided a primer on the basics of this technology in In re O’Farrell, 853 F.2d 894,
895-99    (Fed.    Cir.    1988).   Specifically,   appellants   claim   DNA    molecules

(“polynucleotides”) encoding a protein (“polypeptide”) known as the Natural Killer Cell

Activation Inducing Ligand (“NAIL”).

       Natural Killer (“NK”) cells, thought to originate in the bone marrow, are a class of

cytotoxic lymphocytes that play a major role in fighting tumors and viruses. NK cells

express a number of surface molecules which, when stimulated, can activate cytotoxic

mechanisms. NAIL is a specific receptor protein on the cell surface that plays a role in

activating the NK cells.

       The specification of the claimed invention recites an amino acid sequence of a

NAIL polypeptide. The invention further isolates and sequences a polynucleotide that

encodes a NAIL polypeptide. Moreover, the inventors trumpet their alleged discovery of

a binding relationship between NAIL and a protein known as CD48. The NAIL-CD48

interaction has important biological consequences for NK cells, including an increase in

cell cytotoxicity and in production of interferon. Representative claim 73 of appellants’

application claims the DNA that encodes the CD48-binding region of NAIL proteins:

       73. An isolated nucleic acid molecule comprising a polynucleotide
       encoding a polypeptide at least 80% identical to amino acids 22-221 of
       SEQ ID NO:2, wherein the polypeptide binds CD48.

In other words, appellants claim a genus of isolated polynucleotides encoding a protein

that binds CD48 and is at least 80% identical to amino acids 22-221 of SEQ ID NO:2 –

the disclosed amino acid sequence for the CD48-binding region of NAIL.

       Appellants’ specification discloses nucleotide sequences for two polynucleotides

falling within the scope of the claimed genus, namely SEQ ID NO:1 and SEQ ID NO:3.

SEQ ID NO: 1 recites the specific coding sequence of NAIL, whereas SEQ ID NO: 3



2008-1184                                     2
recites the full NAIL gene, including upstream and downstream non-coding sequences.

The specification also contemplates variants of NAIL that retain the same binding

properties:

      Variants include polypeptides that are substantially homologous to the
      native form, but which have an amino acid sequence different from that of
      the native form because of one or more deletions, insertions or
      substitutions. Particular embodiments include, but are not limited to,
      polypeptides that comprise from one to ten deletions, insertions or
      substitutions of amino acid residues, when compared to a native
      sequence.

      A given amino acid may be replaced, for example, by a residue having
      similar physiochemical characteristics. Examples of such conservative
      substitutions include substitution of one aliphatic residue for another, such
      as Ile, Val, Leu, or Ala for one another; substitutions of one polar residue
      for another, such as between Lys and Arg, Glu and Asp, or Gln and Asn;
      or substitutions of one aromatic residue for another, such as Phe, Trp, or
      Tyr for one another. Other conservative substitutions, e.g., involving
      substitutions of entire regions having similar hydrophobicity
      characteristics, are well known.

’859 Application at 26.   However, the specification does not indicate any example

variants of NAIL that make these conservative amino acid substitutions.

                                           II.

      The Board rejected appellants’ claims as invalid under both § 103 and § 112.

With regard to the § 112 rejection, the Board found the genus of nucleic acids of

representative claim 73 unsupported by an adequate written description.         First, the

Board observed that although appellants had sequenced two nucleic acids falling within

the scope of claim 73, they had not disclosed any variant species where amino acids

22-221 were different in any way from the disclosed SEQ ID NO:2 sequence. Thus, the

Board concluded that appellants were not entitled to their genus claim of DNA

molecules encoding proteins 80% identical to SEQ ID NO:2:



2008-1184                                  3
       [Appellants] have not described what domains of those sequences are
       correlated with the required binding to CD48, and thus have not described
       which of NAIL’s amino acids can be varied and still maintain binding.
       Thus . . . their Specification would not have shown possession of a
       sufficient number of sequences falling within their potentially large genus
       to establish possession of their claimed genus.

       Without a correlation between structure and function, the claim does little
       more than define the claimed invention by function. That is not sufficient
       to satisfy the written description requirement.

Board Decision at 16-17.

       Regarding obviousness, the Board rejected appellants’ claims over the combined

teachings of U.S. Patent No. 5,688,690 (“Valiante”) and 2 Joseph Sambrook et al.,

Molecular Cloning: A Laboratory Manual 43-84 (2d ed. 1989) (“Sambrook”). The Board

also considered, but found to be cumulative to Valiante and Sambrook, Porunelloor

Mathew et al., Cloning and Characterization of the 2B4 Gene Encoding a Molecule

Associated with Non-MHC-Restricted Killing Mediated by Activated Natural Killer Cells

and T Cells, 151 J. Immunology 5328-37 (1993) (“Mathew”).

       Valiante discloses a receptor protein called “p38” that is found on the surface of

human NK cells.      Valiante teaches that the p38 receptor is present on virtually all

human NK cells and “can serve as an activation marker for cytotoxic NK cells.” ‘690

Patent col.3 ll.3-4; see also id. at col.5 ll.6-7 (“Stimulation of p38 results in activation of

cytotoxicity”). Valiante also discloses and claims a monoclonal antibody specific for p38

called “mAB C1.7.” The Board found (and appellants do not dispute) that Valiante’s p38

protein is the same protein as NAIL. Board Decision at 4. A monoclonal antibody is an

antibody that is mass produced in the laboratory from a single clone and that recognizes

only one antigen. Monoclonal antibodies are useful as probes for specifically identifying

and targeting a particular kind of cell.

2008-1184                                     4
       Valiante teaches that “[t]he DNA and protein sequences for the receptor p38 may

be obtained by resort to conventional methodologies known to one of skill in the art.”

‘690 Patent col.7 ll.49-51.

       For example, the receptor may be isolated by immunoprecipitation using
       the mAb C1.7. Alternatively, the receptor may be obtained by prokaryotic
       expression cloning, using the lambda phage gtll, which is described in
       detail in Sambrook et al, Molecular Cloning, A Laboratory Manual, 2d edit.,
       Cold Spring Harbor, N.Y. (1989), pp. 2.43-2.84, incorporated by reference
       herein.

       Additionally, as described in Example 12 below, the DNA sequence
       encoding the receptor can be obtained by the “panning” technique of
       screening a human NK cell library by eukaryotic expression cloning, of
       which several are known. Briefly, plasmids are constructed containing
       random sequences of a human NK cell library which are obtained by
       restriction digestion. Such libraries may be made by conventional
       techniques or may be available commercially.

       Suitable cells, preferably mammalian cells, such as COS-1 cells, are
       transfected with the plasmids and the mAb C1.7 antibody employed to
       identify transfectants containing the receptor after repeated rounds of
       panning. The receptor insert in these cells is then identified and
       sequenced by conventional techniques, such as overlapping deletion
       fragments [Sambrook et al. cited above]. Other known techniques may
       also be employed to sequence the receptor and/or the mAb C1.7.

Id. at col.7 l.51-col.8 l.7. Example 12 of Valiante’s patent further describes a five-step

cloning protocol for “isolating and identifying the p38 receptor.” Id. at col.18 l.6-col.19

l.28. Valiante discloses neither the amino acid sequence of p38 recognized by mAb

C1.7 nor the polynucleotide sequence that encodes p38. Sambrook, incorporated by

reference (as cited above) in Valiante, describes methods for molecular cloning.

Sambrook does not discuss how to clone any particular gene, but provides detailed

instructions on cloning materials and techniques.

       The Mathew reference discloses a cell surface receptor protein called 2B4

“expressed on all NK . . . cells.” Mathew at 5328.        Mathew discloses that 2B4 is

2008-1184                                   5
involved in activating mouse NK cells, and further teaches the “chromosomal mapping,

cloning, expression, and molecular characterization of the 2B4 gene.”       Id. at 5329.

Further, Mathew teaches a monoclonal antibody, mAb 2B4, specific to 2B4, and a

detailed cloning protocol for obtaining the sequence of the gene that codes for the 2B4

protein. Id. at 5328-330. The Board found that Mathew’s signaling molecule 2B4 is the

murine (mouse) version of Valiante’s p38. Board Decision at 5. The Board viewed

Mathew’s teachings to be “cumulative to the teachings in Valiante and Sambrook and

merely . . . exemplary of how routine skill in the art can be utilized to clone and

sequence the cDNA of a similar polypeptide.” Id.

       The Board found as a factual matter that appellants used conventional

techniques “such as those outlined in Sambrook” to isolate and sequence the gene that

codes for NAIL. Id. The Board also found that appellants’ claimed DNA sequence is

“isolated from a cDNA library . . . using the commercial monoclonal antibody C1.7 . . .

disclosed by Valiante.” Id. With regard to the amino acid sequence referred to as SEQ

ID NO:2, the Board found that

       Valiante’s disclosure of the polypeptide p38, and a detailed method of
       isolating its DNA, including disclosure of a specific probe to do so, i.e.,
       mAb C1.7, established Valiante’s possession of p38’s amino acid
       sequence and provided a reasonable expectation of success in obtaining
       a polynucleotide encoding p38, a polynucleotide within the scope of
       Appellants’ claim 73. (See Valiante, col.7, I.48 to col.8, l.7.)

Id. at 6. Because of NAIL’s important role in the human immune response, the Board

further found that “one of ordinary skill in the art would have recognized the value of

isolating NAIL cDNA, and would have been motivated to apply conventional

methodologies, such as those disclosed in Sambrook and utilized in Valiante, to do so.”

Id. at 6-7.

2008-1184                                  6
         Based on these factual findings, the Board turned to the legal question of

obviousness under § 103. Invoking the Supreme Court’s decision in KSR International

Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Board concluded that appellants’ claim

was “‘the product not of innovation but of ordinary skill and common sense,’ leading us

to conclude NAIL cDNA is not patentable as it would have been obvious to isolate it.”

Board Decision at 9 (citing KSR, 550 U.S. at 421).

         Appellants appeal the Board’s decisions both as to obviousness and written

description. This court has jurisdiction under 28 U.S.C. § 1295(a)(4) and 35 U.S.C.

§ 141.

                                             III.

         This court reviews the Board’s factual findings for lack of substantial evidence,

and its legal conclusions without deference. In re Gartside, 203 F.3d 1305, 1315 (Fed.

Cir. 2000).

         Obviousness is a question of law based on underlying findings of fact.          An

analysis of obviousness must be based on several factual inquiries: (1) the scope and

content of the prior art; (2) the differences between the prior art and the claims at issue;

(3) the level of ordinary skill in the art at the time the invention was made; and (4)

objective evidence of nonobviousness, if any. See Graham v. John Deere Co., 383

U.S. 1, 17-18 (1966). The teachings of a prior art reference are underlying factual

questions in the obviousness inquiry. See Para-Ordnance Mfg., Inc. v. SGS Imp. Int’l,

Inc., 73 F.3d 1085, 1088 (Fed. Cir. 1995).




2008-1184                                     7
                                                 A.

       As a factual matter, the Board concluded that appellants’ methodology of

isolating NAIL DNA was essentially the same as the methodologies and teachings of

Valiante and Sambrook. Appellants charge that the record does not contain substantial

evidence to support this Board conclusion.

       This emphasis on similarities or differences in methods of deriving the NAIL DNA

misses the main point of this obviousness question.        Of note, the record nowhere

suggests that the technique in Valiante’s Example 12 for isolating NAIL (p38) DNA,

even if slightly different than the technique disclosed in the claimed invention, would not

yield the same polynucleotide claimed in claim 73. Stated directly, the record shows

repeatedly that Valiante’s Example 12 produces for any person of ordinary skill in this

art the claimed polynucleotide.

       More to the point, however, any putative difference in Valiante’s/Sambrook’s and

appellants’ processes does not directly address the obviousness of representative claim

73, which claims a genus of polynucleotides. The difference between Valiante’s and the

application’s techniques might be directly relevant to obviousness in this case if Kubin

and Goodwin had claimed a method of DNA cloning or isolation. But they did not.

Appellants claim a gene sequence. Accordingly, the obviousness inquiry requires this

court to review the Board’s decision that the claimed sequence, not appellants’

unclaimed cloning technique, is obvious in light of the abundant prior art.

       In any event, this court determines that the Board had substantial evidence to

conclude that appellants used conventional techniques, as taught in Valiante and

Sambrook, to isolate a gene sequence for NAIL. In particular, appellants’ arguments



2008-1184                                    8
that Valiante and Sambrook are deficient because they do not provide “any guidance for

the preparation of cell culture that will serve as a useful source of mRNA for the

preparation of a cDNA library,” Appellants’ Br. 34, are diminished by appellants’ own

disclosure:

      A “nucleotide sequence” refers to a polynucleotide molecule in the form of
      a separate fragment or as a component of a larger nucleic acid construct.
      The nucleic acid molecule has been derived from DNA or RNA isolated at
      least once in substantially pure form and in a quantity or concentration
      enabling identification, manipulation, and recovery of its component
      nucleotide sequences by standard biochemical methods (such as those
      outlined in Sambrook et al., Molecular Cloning: A Laboratory Manual, 2nd
      ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (1989)).

’859 Application at 16-17 (emphasis added).         Thus, Kubin and Goodwin cannot

represent to the public that their claimed gene sequence can be derived and isolated by

“standard biochemical methods” discussed in a well-known manual on cloning

techniques, while at the same time discounting the relevance of that very manual to the

obviousness of their claims. For this reason as well, substantial evidence supports the

Board’s factual finding that “[a]ppellants employed conventional methods, ‘such as

those outlined in Sambrook,’ to isolate a cDNA encoding NAIL and determine the

cDNA’s full nucleotide sequence (SEQ NOS: 1 & 3).” Board Decision at 5.

      In a similar vein, this court reviews the Board’s reference to the teachings of

Mathew and the connection between Mathew’s 2B4 and Valiante’s p38 proteins. As an

initial point, the Board referenced Mathew only as cumulative of Sambrook and

Valiante.     Therefore, the Board’s obviousness analysis does not explicitly rely on

Mathew at all. Instead the Board observed that Mathew is “exemplary of how routine

skill in the art can be utilized to clone and sequence the cDNA of a similar polypeptide.”

Id. In that connection, the record shows that a researcher of ordinary skill in this art

2008-1184                                   9
would have recognized that both Valiante and Mathew are indisputably focused on

regulation of NK cells – Mathew with regard to mice and Valiante with regard to

humans.      Like Valiante’s Example 12, Mathew discusses a detailed protocol for

identifying, isolating, and cloning cDNA encoding 2B4, which was later discovered to be

the murine equivalent of Valiante’s p38 and appellants’ NAIL protein.          Moreover,

Mathew expressly states that his genomic DNA blot analysis “identified a human

homologue of the 2B4 gene.” Mathew at 5333. In sum, substantial evidence supports

the Board’s conclusion that Matthew reinforces the relative ease of deriving the claimed

sequence following the teachings of the prior art.

         This court notes that Matthew contains some data that “suggests that [the] 2B4

gene is not expressed in humans.” Id. This part of the record, however, does not

undermine the Board’s correct conclusion that Mathew does not “teach away” from

combining its teachings with Valiante. “A reference may be said to teach away when a

person of ordinary skill, upon reading the reference, would be discouraged from

following the path set out in the reference, or would be led in a direction divergent from

the path that was taken by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir.

1994).     According to Mathew, “[i]t appears . . . that the 2B4 gene is somewhat

conserved during evolution.” Mathew at 5335. Mathew’s quasi-agnostic stance toward

the existence of a human homologue of the 2B4 gene cannot fairly be seen as

dissuading one of ordinary skill in the art from combining Mathew’s teachings with those

of Valiante. Rather, Mathew’s disclosure, in light of Valiante’s teachings regarding the

p38 protein and its role in NK cell activation, would have aroused a skilled artisan’s

curiosity to isolate the gene coding for p38. Thus, the record supplies ample evidence



2008-1184                                   10
to support the Board’s finding that Mathew “exemplifies how the cDNA encoding 2B4,

the mouse version of Valiante’s p38 expressed on all NK cells, can be isolated and

sequenced.” Board Decision at 10.

          This court also observes that the Board had no obligation to predicate its

obviousness finding on factual findings regarding a prior art teaching of NAIL’s binding

to the CD48 protein. Even if no prior art of record explicitly discusses the “wherein the

polypeptide binds CD48” aspect of claim 73, the Kubin-Goodwin application itself

instructs that CD48 binding is not an additional requirement imposed by the claims on

the NAIL protein, but rather a property necessarily present in NAIL. See, e.g., ’859

Application at 1, 8 (describing CD48 as NAIL’s “counterstructure”). Because this court

sustains, under substantial evidence review, the Board’s finding that Valiante’s p38 is

the same protein as appellant’s NAIL, Valiante’s teaching to obtain cDNA encoding p38

also necessarily teaches one to obtain cDNA of NAIL that exhibits the CD48 binding

property. See, e.g., Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249

(1945) (“It is not invention to perceive that the product which others had discovered had

qualities they failed to detect.”); In re Wiseman, 596 F.2d 1019, 1023 (CCPA 1979)

(rejecting the notion that “a structure suggested by the prior art, and, hence,

potentially in the possession of the public, is patentable . . . because it also possesses

an inherent, but hitherto unknown, function which [patentees] claim to have discovered.

This is not the law. A patent on such a structure would remove from the public that

which is in the public domain by virtue of its inclusion in, or obviousness from, the prior

art.”).




2008-1184                                   11
                                              B.

       The instant case also requires this court to consider the Board’s application of

this court’s early assessment of obviousness in the context of classical biotechnological

inventions, specifically In re Deuel, 51 F.3d 1552 (Fed. Cir. 1995). In Deuel, this court

reversed the Board’s conclusion that a prior art reference teaching a method of gene

cloning, together with a reference disclosing a partial amino acid sequence of a protein,

rendered DNA molecules encoding the protein obvious. Id. at 1559. In reversing the

Board, this court in Deuel held that “knowledge of a protein does not give one a

conception of a particular DNA encoding it.” Id. Further, this court stated that “obvious

to try” is an inappropriate test for obviousness.

   [T]he existence of a general method of isolating cDNA or DNA molecules is
   essentially irrelevant to the question whether the specific molecules
   themselves would have been obvious, in the absence of other prior art that
   suggests the claimed DNAs. . . . “Obvious to try” has long been held not to
   constitute obviousness. A general incentive does not make obvious a
   particular result, nor does the existence of techniques by which those efforts
   can be carried out.

Id. (internal citations omitted) (emphases added).      Thus, this court must examine

Deuel’s effect on the Board’s conclusion that Valiante’s teaching of the NAIL protein,

combined with Valiante’s/Sambrook’s teaching of a method to isolate the gene

sequence that codes for NAIL, renders claim 73 obvious.

       With regard to Deuel, the Board addressed directly its application in this case. In

particular, the Board observed that the Supreme Court in KSR cast doubts on this

court’s application of the “obvious to try” doctrine:

       To the extent Deuel is considered relevant to this case, we note the
       Supreme Court recently cast doubt on the viability of Deuel to the extent
       the Federal Circuit rejected an ‘”obvious to try” test. See KSR Int’l Co. v.
       Teleflex Inc., 127 S. Ct. 1727, __, 82 U.S.P.Q. 2d 1385, 1394, 1396

2008-1184                                     12
      (2007) (citing Deuel, 51, F.3d at 1559). Under KSR, it’s now apparent
      “obvious to try” may be an appropriate test in more situations than we
      previously contemplated.

Board Decision at 8. Insofar as Deuel implies the obviousness inquiry cannot consider

that the combination of the claim’s constituent elements was “obvious to try,” the

Supreme Court in KSR unambiguously discredited that holding. In fact, the Supreme

Court expressly invoked Deuel as a source of the discredited “obvious to try” doctrine.

The KSR Court reviewed this court’s rejection, based on Deuel, of evidence showing

that a particular combination of prior art elements was obvious because it would have

been obvious to one of ordinary skill in the art to attempt such a combination:

      The only declaration offered by KSR—a declaration by its Vice President
      of Design Engineering, Larry Willemsen—did not go to the ultimate issue
      of motivation to combine prior art, i.e. whether one of ordinary skill in the
      art would have been motivated to attach an electronic control to the
      support bracket of the assembly disclosed by Asano. Mr. Willemsen did
      state that an electronic control “could have been” mounted on the support
      bracket of a pedal assembly. (Willemsen Decl. at P33, 36, 39.) Such
      testimony is not sufficient to support a finding of obviousness, however.
      See, e.g., In re Deuel, 51 F.3d 1552, 1559 (Fed. Cir. 1995) (“‘Obvious to
      try’ has long been held not to constitute obviousness.”).

Teleflex, Inc. v. KSR Int’l Co., 119 F. App’x 282, 289 (Fed. Cir. 2005). The Supreme

Court repudiated as “error” the Deuel restriction on the ability of a skilled artisan to

combine elements within the scope of the prior art:

      The same constricted analysis led the Court of Appeals to conclude, in
      error, that a patent claim cannot be proved obvious merely by showing
      that the combination of elements was “obvious to try.” When there is a
      design need or market pressure to solve a problem and there are a finite
      number of identified, predictable solutions, a person of ordinary skill has
      good reason to pursue the known options within his or her technical grasp.
      If this leads to the anticipated success, it is likely the product not of
      innovation but of ordinary skill and common sense. In that instance the
      fact that a combination was obvious to try might show that it was obvious
      under § 103.



2008-1184                                  13
KSR, 550 U.S. at 421 (internal citation omitted) (emphasis added).

        The Supreme Court’s admonition against a formalistic approach to obviousness

in this context actually resurrects this court’s own wisdom in In re O’Farrell, which

predates the Deuel decision by some seven years. This court in O’Farrell cautioned

that “obvious to try” is an incantation whose meaning is often misunderstood:

        It is true that this court and its predecessors have repeatedly emphasized
        that “obvious to try” is not the standard under § 103. However, the
        meaning of this maxim is sometimes lost. Any invention that would in fact
        have been obvious under § 103 would also have been, in a sense,
        obvious to try. The question is: when is an invention that was obvious to
        try nevertheless nonobvious?

In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). To differentiate between proper and

improper applications of “obvious to try,” this court outlined two classes of situations

where “obvious to try” is erroneously equated with obviousness under § 103. In the first

class of cases,

        what would have been “obvious to try” would have been to vary all
        parameters or try each of numerous possible choices until one possibly
        arrived at a successful result, where the prior art gave either no indication
        of which parameters were critical or no direction as to which of many
        possible choices is likely to be successful.

Id. In such circumstances, where a defendant merely throws metaphorical darts at a

board filled with combinatorial prior art possibilities, courts should not succumb to

hindsight claims of obviousness.         The inverse of this proposition is succinctly

encapsulated by the Supreme Court’s statement in KSR that where a skilled artisan

merely pursues “known options” from a “finite number of identified, predictable

solutions,” obviousness under § 103 arises. 550 U.S. at 421.

        The second class of O’Farrell’s impermissible “obvious to try” situations occurs

where

2008-1184                                    14
       what was “obvious to try” was to explore a new technology or general
       approach that seemed to be a promising field of experimentation, where
       the prior art gave only general guidance as to the particular form of the
       claimed invention or how to achieve it.

853 F.2d at 903. Again, KSR affirmed the logical inverse of this statement by stating

that § 103 bars patentability unless “the improvement is more than the predictable use

of prior art elements according to their established functions.” 550 U.S. at 417.

       This court in O’Farrell found the patentee’s claims obvious because the Board’s

rejection of the patentee’s claims had not presented either of the two common “obvious

to try” pitfalls.   Specifically, this court observed that an obviousness finding was

appropriate where the prior art “contained detailed enabling methodology for practicing

the claimed invention, a suggestion to modify the prior art to practice the claimed

invention, and evidence suggesting that it would be successful.”          853 F.2d at 902

(emphasis added).       Responding to concerns about uncertainty in the prior art

influencing the purported success of the claimed combination, this court stated:

“[o]bviousness does not require absolute predictability of success . . . all that is required

is a reasonable expectation of success.”          Id. at 903-04 (emphasis added).       The

Supreme Court in KSR reinvigorated this perceptive analysis.

       KSR and O’Farrell directly implicate the instant case.         Appellants’ claim 73

recites a genus of isolated nucleic acid molecules encoding the NAIL protein. As found

by the Board, the Valiante reference discloses the very protein of appellants’ interest –

”p38” as per Valiante. Board Decision at 4. Valiante discloses a monoclonal antibody

mAb C1.7 that is specific for p38/NAIL, and further teaches a five-step protocol for

cloning nucleic acid molecules encoding p38/NAIL using mAb C1.7. Id. In fact, while

stating that “[t]he DNA and protein sequences for the receptor p38 may be obtained by

2008-1184                                    15
resort to conventional methodologies known to one of skill in the art,” ‘690 Patent at

col.7 ll.49-51, Valiante cites to the very same cloning manual, Sambrook, cited by Kubin

and Goodwin for their proposition that the gene sequence is identified and recovered

“by standard biochemical methods.”       ’859 Application at 16.     Moreover, the record

strongly reinforces (and appellants apparently find no room to dispute) the Board’s

factual finding that one of ordinary skill would have been motivated to isolate NAIL

cDNA, given Valiante’s teaching that p38 is “expressed by virtually all human NK cells

and thus plays a role in the immune response.” Board Decision at 6. The record shows

that the prior art teaches a protein of interest, a motivation to isolate the gene coding for

that protein, and illustrative instructions to use a monoclonal antibody specific to the

protein for cloning this gene. Therefore, the claimed invention is “the product not of

innovation but of ordinary skill and common sense.” KSR, 550 U.S. at 421. Or stated in

the familiar terms of this court’s longstanding case law, the record shows that a skilled

artisan would have had a resoundingly “reasonable expectation of success” in deriving

the claimed invention in light of the teachings of the prior art. See O’Farrell, 853 F.2d at

904.

       This court also declines to cabin KSR to the “predictable arts” (as opposed to the

“unpredictable art” of biotechnology). In fact, this record shows that one of skill in this

advanced art would find these claimed “results” profoundly “predictable.” The record

shows the well-known and reliable nature of the cloning and sequencing techniques in

the prior art, not to mention the readily knowable and obtainable structure of an

identified protein.    Therefore this court cannot deem irrelevant the ease and

predictability of cloning the gene that codes for that protein. This court cannot, in the



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face of KSR, cling to formalistic rules for obviousness, customize its legal tests for

specific scientific fields in ways that deem entire classes of prior art teachings irrelevant,

or discount the significant abilities of artisans of ordinary skill in an advanced area of art.

See In re Durden, 763 F.2d 1406, 1411 (Fed. Cir. 1985) (“Our function is to apply, in

each case, § 103 as written to the facts of disputed issues, not to generalize or make

rules for other cases which are unforeseeable.”). As this court’s predecessor stated in

In re Papesch, “[t]he problem of ‘obviousness’ under section 103 in determining the

patentability of new and useful chemical compounds . . . is not really a problem in

chemistry or pharmacology or in any other related field of science such as biology,

biochemistry, pharmacodynamics, ecology, or others yet to be conceived.                It is a

problem of patent law.” 315 F.2d 381, 386 (CCPA 1963).

       The record in this case shows that Valiante did not explicitly supply an amino

acid sequence for NAIL or a polynucleotide sequence for the NAIL gene. In that sense,

Kubin and Goodwin’s disclosure represents some minor advance in the art.                   But

“[g]ranting patent protection to advances that would occur in the ordinary course without

real innovation retards progress.” KSR, 550 U.S. at 419. “Were it otherwise patents

might stifle, rather than promote, the progress of useful arts.” Id. at 427. In light of the

concrete, specific teachings of Sambrook and Valiante, artisans in this field, as found by

the Board in its expertise, had every motivation to seek and every reasonable

expectation of success in achieving the sequence of the claimed invention. In that

sense, the claimed invention was reasonably expected in light of the prior art and

“obvious to try.” See Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc., 520 F.3d 1358,

1364 (Fed. Cir. 2008) (“KSR posits a situation with a finite, and in the context of the art,



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small or easily traversed, number of options that would convince an ordinarily skilled

artisan of obviousness.”). These references, which together teach a protein identical to

NAIL, a commercially available monoclonal antibody specific for NAIL, and explicit

instructions for obtaining the DNA sequence for NAIL, are not analogous to prior art that

gives “no direction as to which of many possible choices is likely to be successful” or

“only general guidance as to the particular form of the claimed invention or how to

achieve it.” O’Farrell, 853 F.2d at 903. As the Board found, the prior art here provides

a “reasonable expectation of success” for obtaining a polynucleotide within the scope of

claim 73, Board Decision at 6, which, “[f]or obviousness under § 103 [is] all that is

required.” O’Farrell, 853 F.2d at 903. Thus, this court affirms the Board’s conclusion as

to obviousness.

                                              IV.

       For the reasons stated above, the Board did not err in finding appellants’ claims

obvious as a matter of law. Thus, this court need not address appellants’ contention

that the Board erred in finding its claims invalid under § 112 ¶ 1. Accordingly, this court

affirms the decision of the Board.



                                       AFFIRMED



                                         COSTS

       Each party shall bear its own costs.




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