Abraham J. Rosner and Dean H. Nakamura
Sughrue, Mion, Zinn, Macpeak & Seas
Gaikoku-Jimu-Bengoshi Jimusho

In this technique, a foreign (e.g., human) gene which contains instructions for making a desired protein (e.g., a human hormone such as insulin) is identified and isolated from a "library" containing a set of DNA sequences present in a human cell. This is called "cloning."⁵

The foreign genetic material is inserted into the DNA (genetic material) of a bacterium or "host" cell by means of a carrier (vector). This is called "transforming" or "transfecting" the host cells.⁶

Some of the genetically altered bacteria will produce the desired human protein, along with all of the other substances that the bacteria would ordinarily make. The bacteria are screened by growing cultures from single-cell derived colonies, and selecting those which produce the desired protein. The selected bacteria are grown in large vats, and are then "harvested" to recover the desired protein.

2. Monoclonal Antibodies

More particularly, this might involve culturing a hybridoma (fused cell), to thereby produce a monoclonal antibody. In this case, the hybridoma may be novel and unobvious (i.e., patentable), however, the process to make the hybridoma itself is known.

Monoclonal antibodies are antibodies (proteins) produced by a culture derived from a single cell.⁷ These antibodies recognize a single determinant or structure of a given antigen.⁸

In a general procedure for producing monoclonal antibodies, a mouse is immunized with a purified antigen or a mixture of antigens. Spleen cells or lymphocytes (which produce antibodies but cannot be cultured in vitro) from the immunized mouse are fused in the presence of polyethylene glycol with mouse myeloma cells (malignant tumor cells of the immune system) deficient in a certain type of enzyme. The myeloma cells can be cultured in vitro, but die in the presence of a growth medium containing a certain chemical substance due to the enzyme deficiency. However, the spleen cells produce this enzyme. Thus, myeloma cells which fuse with spleen cells to form a heterocaryon are able to survive.

After fusion, the cells are distributed into individual cell cultures containing the selective growth medium and are incubated. Only those cells that have been successfully fused will grow. Two-to four weeks later, the culture medium from the growing cells (the hybrids) is examined for the presence of the specific antibody of interest. Cultures positive for the desired antibody, which are called hybridomas, are "cloned" or purified. The clones may be grown in large tissue cultures to produce the antibody, or injected into animals to produce myelomas that secrete the antibody.⁹

3. Legislative Reaction to the Court Decision of In re Durden

The Federal Circuit in In re Durden, 226 USPQ 359 (Fed. Cir. 1985), held that a chemical process is not necessarily patentable even though the specific starting material employed in the process and/or the product obtained by the process are novel and unobvious. Rather, according to the court, patentability would instead depend on whether or not the claimed process itself is unobvious (e.g., unpredictable). The new law effectively repeals the decision of In re Durden with respect to the biotechnological processes defined therein.

Biotech companies could readily obtain claims, for example, directed to a purified and isolated DNA sequence encoding a particular protein (recombinant DNA), or to a transformed host cell containing a recombinant DNA sequence (host cell), or to a recombinant DNA vector which is capable of expressing the encoded protein (vector). However, biotech companies would often use processes that produce predictable results to achieve the desired end product, namely, inserting a foreign gene into a cell line and culturing the cell line to produce a protein. Also, the end product, a purified protein, may already have been patented or described in the prior art, or found in nature.

Pursuant the decision in In re Durden, the PTO would often reject (or inconsistently reject) claims drawn to a method for producing a protein, comprising the steps of culturing the host cell and harvesting the protein from the culture, as being unpatentable (i.e., an otherwise obvious process which produces predictable results, where the host cell employed as a starting material is novel and unobvious).

4. Effect of the New Legislation

Consider a biotech company which has a patent covering the transformed host cell and vector, but does not have a patent covering the purified protein itself. In that situation, third parties would be free to make the protein abroad using the patented host cell and then sell the protein in the United States. Thus, without process patent protection, importation of the final product (protein) could not be challenged.¹⁰

A specific example is found in the decision of Amgen Inc. v. U.S. International Trade Commission, 14 USPQ2d 1734 (Fed. Cir. 1990). Therein, the court held that Amgen's product patent directed to a transformed host cell and recombinant DNA sequence did not cover recombinant erythropoietin (EPO) which was made in Japan using the patented host cells and then exported to the United States. That is, the patented host cells were used in Japan but not in the United States. More particularly, Amgen unsuccessfully argued that the law prohibits imports made by a process using patented articles (as opposed to imported articles that are made using a patented process).

Amgen's experience with EPO was one of the events leading to the introduction and passage of the Biotechnology Process Patents Bill.

Part of the rationale behind the bill is that biotech companies would be more willing to make large investments in research if they had the assurance of receiving a process patent. Also, the legislation was enacted to prevent foreign firms from expropriating inventions made in the United States (producing a protein abroad using a patented host cell), and directly competing in the United States with the inventing firm (the firm that invented the host cell).¹¹

Thus, the new law will allow biotech companies to obtain process patents which cover, for example, a method of producing a protein using a novel and unobvious transformed host cell. In that case, a third party would still be free to produce the protein abroad using the patented host cell. However, the patent holder could sue for damages for patent infringement or request the court to grant an injunction if the protein made abroad is imported, sold or used in the United States under 35 U.S.C. §271(g), and the patent holder could block import of the protein under 19 U.S.C. §1337.¹²

Section 103 of title 35, United States code is amended--

1. by designating the first paragraph as subsection (a);
2. by designating the second paragraph as subsection (c); and
3. by inserting after the first paragraph the following:

(b)(1) Notwithstanding subsection (a), and upon timely election by the applicant for patent to proceed under this subsection, a biotechnological process using or resulting in a composition of matter that is novel under section 102 and nonobvious under subsection (a) of this section shall be considered nonobvious if--

1. claims to the process and the composition of matter are contained in either the same application for patent or in separate applications having the same effective filling date; and
2. the composition of matter, and the process at the time it was invented, were owned by the same person or subject to an obligation of assignment to the same person.

(2) A patent issued on a process under paragraph (1)--

3. shall also contain the claims to the composition of matter used in or made by that process, or
4. shall, if such composition of matter is claimed in another patent, be set to expire on the same date as such other patent, notwithstanding section 154.

(3) For purposes of paragraph (1), the term "biotechnological process" means--

5. a process of genetically altering or otherwise inducing a single- or multi-celled organism to--
1. express an exogenous¹³ nucleotide sequence,
2. inhibit, eliminate, augment, or alter expression of an endogenous¹⁴ nucleotide sequence, or
3. express a specific physiological characteristic not naturally associated with said organism;
6. cell fusion procedures yielding a cell line that expresses a specific protein, such as a monoclonal antibody; and
7. a method of using a product produced by a process defined by (A) or (B), or a combination of (A) and (B).

Section 2. Presumption of Validity; Defenses.

Section 282 of title 35, United States code, is amended by inserting after the second sentence of the first paragraph the following:

Notwithstanding the preceding sentence, if a claim to a composition of matter is held invalid and that claim was the basis of a determination of nonobviousness under section 103(b)(1), the process shall no longer be considered nonobvious solely on the basis of section 103(b)(1).

Section 3. Effective Date.

The amendments made by section 1 shall apply to any application for patent filed on or after the date of enactment of this Act and to any application for patent pending on such date of enactment, including (in either case) an application for the reissuance of a patent.

This was an appeal from the decision of the Board of Appeals affirming the examiner's rejection of process claims over the prior art.

The appellants obtained a patent directed to novel and unobvious oxime compounds (starting material) and another patent directed to novel and unobvious carbamate compounds (insecticidal end product). However, the PTO examiner rejected the appellants' claims directed to a process of making the novel carbamate products from the novel oxime starting materials. In the examiner's view, the prior art disclosed a similar process, and there was no evidence that the novel starting materials would react differently than those taught by the prior art.

The appellants conceded that the claimed process, apart from employing a novel and unobvious starting material and apart from producing a new and unobvious product is obvious. The appellants did not argue that differences in the chemical structure of either the starting material or product produced would be expected to affect the reaction in any way which might render the claimed process unobvious.

2. The Issue

The issue was whether a chemical process, otherwise obvious, is patentable because either or both the specific starting material employed and the product obtained are novel and unobvious.

Pursuant the decision of In re Durden, the PTO would often reject (or inconsistently reject) claims drawn to a method for producing a protein, comprising the steps of culturing the transformed host cell and harvesting the protein from the culture, as being unpatentable (i.e., an otherwise obvious process which produces predictable results, even though the host cell employed as a starting material was novel and unobvious).

Several types of claims can be made for this type of invention. These include:

Amgen owned U.S. Patent No. 4,703,008 (the '008 patent) containing claims directed to purified and isolated DNA sequences encoding EPO, as well as claims directed to host cells transformed with a DNA sequence (recombinant DNA technology). However, Amgen's claims directed to a process for producing EPO comprising culturing the transformed host cells and recovering the protein were rejected during prosecution in the PTO under authority of In re Durden.

Genetics Institute owned U.S. Patent 4,677,195 (the '195 patent) containing claims directed to compositions comprised of highly purified EPO. The patent was licensed by Chugai. The purified protein was obtained from urine and purified by HPLC (high performance liquid chromatography).

2. Amgen, Inc. v. Chugai Pharmaceutical Co., 9 USPQ2d 1833 (D. Mass. 1989)

The court held that Amgen's recombinant EPO infringed the '195 protein patent. That is, the EPO produced by the recombinant technique was found to be the same as the EPO claimed in the '195 patent.

The court also held that the '008 patent does not contain process claims, and more specifically that the '008 patent does not contain a process claim covering the process of manufacturing recombinant EPO.

In this regard, the court noted that during prosecution of the '008 patent the PTO rejected Amgen's process claims as being unpatentable under the authority of In re Durden. Amgen subsequently cancelled the process claims for possible presentation in a continuation application.

The court further noted that if Chugai used host cells covered by the claims of the '008 patent in its production of recombinant EPO, and such production was conducted in the United States, then use of the patented host cells would infringe the '008 patent.

3. Amgen, Inc. v. International Trade Commission, 14 USPQ2d 1734 (Fed. Cir. 1990)

Amgen filed a complaint with the USITC alleging that Chugai had violated section 337 by importing recombinant EPO made by a "process" covered by the '008 patent.

The court held that Amgen's complaint under section 337 should be dismissed, and remanded the case to the USITC. In their decision, the court found that Amgen's patent containing claims directed to transformed host cells and a DNA sequence encoding EPO did not include any process claims.

Thus, although importing a product made abroad by a patented process is an unfair trade practice under 337, the court noted that section 337 did not prohibit the importation of goods made abroad by a process using a patented product or material.

The Biotechnology Process Patents Bill will facilitate the issuance of process patents in the biotechnology field, and effectively repeals the decision of the Federal Circuit in In re Durden with respect to patentability of biotechnological processes. Consequently, the new law will make it possible for patent owners holding U.S. biotech process patents to bar as infringements imported biotech products made abroad using the patented process. The expectation of the Congress is that the new law will provide patent protection that biotech companies need to continue to develop new products, and that the public will benefit from the resulting improvements in the diagnosis, cure and treatment of disease.

1) The term "exogenous" means introduced from another organism.

2) The term "endogenous" means originating from within the organism.

3) The term "recombinant" refers to joining DNA pieces that are not normally found together (e.g., DNA from two different species). Within each eucaryotic cell is a nucleus which contains chromosomes. DNA (deoxyribonucleic acid) is the genetic material in the chromosomes which controls and determines everything that the cell is made of and everything that it does. DNA is a long chain molecule made of many shorter pieces called "genes". A gene is a portion of the DNA molecule which, for example, is responsible for directing the synthesis of a protein. The molecular structure of DNA includes a backbone of alternating sugar and phosphate groups with nitrogenous nucleotides or bases attached to the sugar residues. In DNA, there are four kinds of nucleotides, including thymine (T), cytosine (C), guanine (G) and adenine (A).

DNA is composed of two complementary strands which coil around each other in a double helix. The bases on one strand weakly bond (hydrogen bonding) to complementary bases of the opposite strand. If A is the base on one chain, the corresponding base in the other chain is T. If C is the base in one chain, the corresponding base in the other chain is G. These are called complementary base pairs, and the bonding process is called hybridization.

4) For example, EPO (erythropoietin) is a hormone which stimulates red blood cell production. EPO is made in the kidney and circulates through the blood stream to the sites where blood cells are made. It is useful in treating a type of anemia which results from renal (kidney) failure. Very small amounts of EPO can be recovered and purified from urine. However, the amounts that can be recovered from natural sources are insufficient to be useful in treating disease. A hormone is a protein that is made and secreted from one type of cell, travels through the bloodstream, and then acts on cells in another organ (carries messages from one organ of the body to another).

5) In somewhat more detail, proteins are composed of one or more amino acid chains or polypeptides which have a three dimensional (folded) shape. There are twenty different kinds of naturally occurring amino acids. A typical protein may comprise a chain of several hundred amino acids. Genes contain the information needed to direct protein synthesis. That is, a gene contains data which specifies the amino acid sequence of the protein (type and position of each amino acid in the protein).

The genetic code for a particular protein having a specific amino acid sequence is determined by sequential groups of nucleotides called "codons". Each codon is a sequential group of three nucleotides, and each group of three codes for an amino acid. For example, the codon sequence CAA may code for the amino acid valine. Since there are four nucleotide bases and three bases per codon, there are 64 possible codons. Furthermore, because there are only 20 naturally occurring amino acids, many amino acids are specified by more than one codon. This is called "degeneracy" in the genetic code.

Cloning a gene means identifying or "isolating" the portion of the double helix which contains the DNA sequence that the cell uses to create a particular protein from the rest of its DNA material. This is done by screening a DNA "library" with a "probe".

A DNA library, for example, contains human DNA that is broken up into many random, smaller segments. One of these segments may contain the gene which codes for the protein. The segments are inserted into a carrier capable of independent survival in a host cell. Ideally, each carrier will contain different pieces of human DNA. The engineered carrier is then placed in a cell for propagation. Typically, a DNA library is a test tube of bacteria each carrying a "vector" that contains a different segment of the foreign (human) DNA.

A probe is a synthetic, labeled nucleic acid sequence which is used to detect and isolate complementary base sequences of the library's DNA by hybridization. A "probe" is synthesized by assembling a sequence of nucleotides in codon groups corresponding to consecutive amino acids in the protein (or a portion thereof). One strategy is to prepare a set of probes which cover all of the possible groups of three nucleotides that code for each of the particular amino acids comprising the protein. This is known as a "fully degenerate" set of probes.

The library bacteria are spread thinly on petri dishes so that a single bacterium is separated from its neighbors and can grow clonally to produce a mass of identical bacteria. A membrane is laid on the top of each dish to allow some of the bacteria to adhere to the membrane. The bacterial cells on the membranes are lysed, and the DNA contained therein is made single stranded and affixed to the membrane. It is these membranes which are exposed to the probe. The probe will bind with a high degree of specificity to the gene associated with the protein. That is, if there is a complementary match between a DNA strand of the library and the probe, the probe will hybridize (bind) to the DNA segment. The locations where the probe binds are identified by radiography when the probe is radiolabeled, and then cross-referenced to the source colony in the dish. In this way the probe identifies or isolates the gene (or rather the segment of DNA containing the gene) which codes for the desired protein to a specific colony.

6) One type of vector is a "plasmid" which is a small circular piece of DNA which exists in some types of bacteria. Plasmids remain separate from the bacterial chromosome carrying genes for autonomous existence, but are capable of directing protein synthesis. Plasmids replicate and are passed on to daughter cells. The plasmid is removed from the bacteria and cleaved (cut open) with an enzyme. Foreign DNA (e.g., a human DNA segment) is then inserted, and the ring is closed again by other enzymes. The plasmid "vector" is then reinserted into the bacteria.

Another kind of vector is a bacteriophage which is a virus which uses bacteria as a host. The foreign DNA (e.g., human DNA segment) can be inserted into phage genome. When the phage multiplies in a bacterium and eventually kills the bacterium, the foreign piece of DNA is "amplified" into many copies.

7) Antibodies are normally present in the body or produced in response to infection or the introduction of other antigens (e.g., bacteria, toxins, foreign red blood cells). Various antibodies can neutralize certain types of toxins, agglutinate (adhere to) bacteria or foreign cells and precipitate soluble antigens.

8) When an animal is injected with an immunizing agent (antigen), it responds by making diverse antibodies directed against different parts (determinants) of the antigen. Antisera containing a mixture of antibodies is called "polyclonal" antisera. That is, different lymphocytes (immune function cells) in the body produce antibodies directed against different parts of the antigen. Each lymphocyte produces only one type of antibody.

9) Monoclonal antibodies are very useful for removing and purifying plasma proteins. In a general purification method, monoclonal antibodies specific for the protein of interest are attached to the beads of a liquid chromatography column. Plasma containing small amounts of the protein is passed through the column. The protein binds to the antibodies that are fixed to the beads while the rest of the plasma flows through the column. Then, the bound protein is eluted from the column.

10) If the biotech company also had a process patent covering a method of producing the recombinant protein comprising culturing the transformed host cell, the biotech company could challenge importation of the final product (protein) under 35 U.S.C. §271(g). This section of the patent statute provides, in part, that it is an act of infringement to import into the United States or sell within the United States a product (e.g., recombinant protein) which is made by a process patented in the United States.

11) Cong. Rec. 10/17/95, H10095.

12) 35 U.S.C. §271(g) provides, in part, that:

Also, under 19 U.S.C. §1337, the International Trade Commission has the authority to investigate allegations that foreign importers are engaging in unfair methods of competition or infringing a U.S. patent. The importation and sale of an unpatented product produced abroad by a process covered by a U.S. patent is one such unfair act or method of competition, and the ITC has the authority to exclude the product from entry into the United States.

13) The term "exogenous" means introduced from another organism.

14) The term "endogenous" means originating from within the organism.

15) This litigation involved a series of decisions reported at 9 USPQ2d 1833, 10 USPQ2d 1906, 13 USPQ2d 1737, 14 USPQ2d 1734 and 18 USPQ2d 1016