Personalised treatment with customised medical treatment is a fast growing area of health care. It opens up an innovative yet unexplored method of improved treatment with a promise to reduce cost by tailoring a patient's specific characteristics to a particular medical treatment. Though many attempts are being made to get a positive result on patent eligibility, the future of customised medicines still remains uncertain. But the recent decision of US Fed. Circuit in Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals, [887 F.3d 1117] in April, 2018, has given new lease of life to the question of patent eligibility of Personalised Medicine Treatment (PMT) and perhaps laid a foundation for grant of such patents. More so USPTO was quick to issued new guidelines for examination in June 2018 to implement this judicial ruling in such type of other patent applications in USPTO. In India the IPO is still looking West to keep method of treatment as non-eligible for patent protection. The future of patent eligibility of personalized medicine in US seems bright but in other jurisdiction it still faces uncertainty.
Canavan gene patent controversy
In 1994 canvan gene was discovered which was responsible for genetic disorder Canavan disease, a fatal, autosomal recessive, degenerative brain disorder genetically attributed to Dan Greenberg family. In 1997, Miami Children's Hospital (MCH) received a patent for Canavan carrier testing on the Canavan gene and mutations causing the disorder. Dan Greenberg family and the other Canavan families who initially hired Dr. Reuben Matalon, to work on discovering the cause for this genetic disease, challenged the ownership and licensing of the Canavan gene in court. Though their challenge was limited to the ownership and licensing of the Canavan gene yet it raised the pertinent question of right on the gene itself. In fact MCH was forced to enter into a confidential settlement between Dan Greenberg family and the other Canavan families to allow license-free use of the Canavan gene for research purposes. This agreement allowed MCH to collect licensing and royalty fee from other users for clinical testing for Canavan gene mutations. This case showcased how the disease-specific community groups took steps to protect their interests while allowing meaningful contributions to the research by private research groups.
Simple Medical treatment vs personalised treatment
Simple methods of medical treatments that are usually carried out by physicians and surgeons as routine may not have potential to signal further development which may not find favour with patent offices. Such medical procedures are rightly culled out as non-patentable subject matter. However, the medical procedures such as bone marrow transplantation for its effective usefulness in treating leukaemia, anaemia and sickle cell disease do have strong prospective of further refinement though innovations. Similarly gene therapy and embryonic cloning have enough potential to eliminate or cure many currently incurable diseases. The attempt to patent ESTs were not successful because short sequence from a randomly isolated portion of a gene encoding a protein of unknown function did not pass the essential utility test. These rejections were based on first, there was nothing novel about the identification of the ESTs and second picking up EST from a large number of cDNA clones and using such short piece as a genetic marker or tag is known and obvious approach in the state of art. But patenting of ESTS with genetic information when that information had utility did found acceptability in certain patent jurisdictions. Such patents includes for example, recombinant clones for the production of human proteins (e.g. factor VIII, growth hormone, erythropoietin) and disease gene probes for diagnostic testing, carrier identification and prenatal diagnosis (e.g. cystic fibrosis, muscular dystrophy, fragile X syndrome).
What ails the patent eligibility of PMT?
Personalised treatment in general tends to provide the customised medicine which largely depends on data collected and collated from the diagnostic methods. The useful patient specific information about a protein, gene, or metabolite profile is normally obtained using traditional / specific diagnostic procedures. This patient specific information is useful in prediction of treatment response in the patient. Treatment response at times is seen as natural interaction and such natural relationship is denied patent protection. For example in Mayo ruling US SC observed that the claims in Mayo were not directed to a novel method of treating a disease. Instead, the claims were directed to a diagnostic method based on the "relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm." This "relation is a consequence of the ways in which thiopurine compounds are metabolized by the body—entirely natural processes. And so a patent that simply describes that relation sets forth a natural law." In Mayo the asserted claim only recited administering a thiopurine drug to a patient but the claim as a whole was not directed to the application of a drug to treat a particular disease. Thus the claims so drafted to "use where ever relevant" could not pass the muster to become patent eligible. The asserted claims in Mayo did not go beyond recognizing or indicating a need to increase or decrease a dose. It was invalidated as it did not recite the use of drug for a particular disease. The claim in Mayo stated that the metabolite level in blood simply "indicates" a need to increase or decrease dosage, without prescribing a specific dosage regimen or other added steps to take as a result of that indication. The Mayo claims were not "method of treatment" claims that practically apply a natural relationship. Invalidation of Mayo patent by US Supreme Court on the ground that method claims for treating autoimmune diseases based on metabolite levels of drugs administered to the patient, are patent-ineligible, as merely reciting a natural law i.e. correlation of metabolite level and drug dosage remained as a road block to patents on PMT in USPTO and other jurisdiction.
Judicial setbacks to enforcement of PMT patents
Many other such patents have suffered judicial setback during enforcement of PMT patent. For example invalidation of Myriad patent claims for an isolated nucleic acid encoding a BRCA1/2 gene were held patent-ineligible by US Supreme Court by ruling them as being product of nature. However, court allowed claims directed specifically to cDNA for the BRCA1 and BRCA2 genes for testing BRCA1 and 2 gene variants to predict inherited risk of breast and ovarian cancer. Many more such patents suffered enforcement shocks with judicial invalidation at US District court or US Federal Circuit in view these decisions. For instance U.S. District Court for the District of Delaware rejected Endo Pharmaceuticals Inc. (patent assignee) patent US 8808737 for methods of using oxymorphone to treat pain in patients with renal impairment. This invalidation was based on the finding that treating pain in patients with renal impairment by measuring the creatine clearance rate and administering an oxymorphone dosage based on the rate found is not creative or inventive step. The only new step recognised in this case was "to tell doctors to adjust the dosage of oxymorphone based upon their discovery of a natural law ... No creative steps or inventive leaps aside from the discovery of a natural law are contemplated here. The patent merely tells doctors to apply the natural law." Similarly the claims for for non-invasive methods of detecting paternally inherited cell-free fetal DNA ("cffDNA") from a blood sample of a pregnant woman were invalidated by a Federal Circuit in Ariosa Diagnostics, Inc. v. Sequenom, Inc., [788 F.3d 1371] case. While the invalidation in this case was based on the reasoning that "only subject matter new and useful" in the method "was the discovery of the presence of cffDNA in maternal plasma or serum." Following the lead of Mayo and Myriad, US district Courts have invalidated many patents directed to similar kind of personal diagnostic methods as ineligible.
Vanda effect on PMT
In Vanda case US Federal Court examined the ruling of Mayo and Myriad in detail to distinguish it from patent eligibility issue in Vanda patent. Court rightly observed in Vanda ruling that in the asserted patent claims in Mayo, "a doctor . . . could violate the patent even if he did not actually alter his treatment decision in the light of the test." The impugned claim in Mayo was not a treatment claim as it was "not limited to instances in which the doctor actually decreases (or increases) the dosage level where the test results suggest that such an adjustment is advisable.". Thus, the claim in Mayo did not involve doctors using the natural relationship between the metabolite levels and lessening "the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm." The claims in Mayo therefore "tie up the doctor's subsequent treatment decision whether that treatment does, or does not, change in light of the inference he has drawn using the correlations. And they threaten to inhibit the development of more refined treatment recommendations. . . . ." The Court further observed that the claim in Mayo stated that the metabolite level in blood simply "indicates" a need to increase or decrease dosage, without prescribing a specific dosage regimen or other added steps to take as a result of that indication. Similarly, the court distinguished Myriad from Vanda stating that in Myriad claims for "a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring." The Court was careful to note that "method claims" and "patents on new applications of knowledge about [particular] genes" were "not implicated by [its] decision." The Court thus ruling in favour of Vanda observed that "The '610 patent does not claim naturally occurring DNA segments. Rather, the asserted claims fall squarely within categories of claims that the Court stated were not implicated by its decision." To further underscore the distinction between method of treatment claims and those in Mayo, the Supreme Court noted that "[u]nlike, say, a typical patent on a new drug or a new way of using an existing drug, the patent claims do not confine their reach to particular applications of those laws." The Federal Circuit distinguished Mayo, in Vanda stating that the Vanda "inventors recognized the relationships between iloperidone, CYP2D6 metabolism, and QTc prolongation, but that is not what they claimed. They claimed an application of that relationship. Unlike the claim at issue in Mayo, the claims here require a treating doctor to administer iloperidone." As a result, the Federal Circuit held the claims in Vanda patent eligible under the first step of the Alice/Mayo framework because the claims "are directed to a method of using iloperidone to treat schizophrenia," rather than being "directed to" a judicial exception."
Question before the court in Vanda case
In the Venda vs Westward case question before The Federal Circuit was to determine whether the asserted claims were ineligible under § 101 of US law because they were directed to a natural relationship between iloperidone, CYP2D6 metabolism and QT prolongation and they are not directed to a judicial exception. In particular the asserted claim is reproduced below:
A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:
determining whether the patient is a CYP2D6 poor metabolizer by:
obtaining or having obtained a biological sample from the patient;
performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and
if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and
if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day,
wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be ifthe iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.
Claim 1 requires specific steps: (1) determining the patient's CYP2D6 metabolizer genotype by (a) obtaining a biological sample and (b) performing a genotyping assay; and (2) administering specific dose ranges of iloperidone depending on the patient's CYP2D6 genotype. This claim recites a method of treating a patient suffering from schizophrenia with iloperidone. The use of Iloperidone in patients having a particular genotype associated with poor drug metabolism is known to cause a disruption of the heart's normal rhythm (QTc prolongation) that can lead to serious health issues. The primary steps according to the court in this patent include "determining" with a genotyping assay, and then "administering" a certain quantity of drug based on that determination, in order to "treat a particular disease." The Federal Circuit then looked at whether the asserted claims were patent-eligible. West-Ward argued that the asserted claims were ineligible under § 101 because they were directed to a natural relationship between iloperidone, CYP2D6 metabolism and QT prolongation. However brushing aside the natural relationship contention of west ward, the Federal Circuit determined that the claims were patent eligible because they "are directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome."
Impact of 'Vanda' on subject matter analysis
The USPTO was quick to issue future guidelines through it MEMORANDUM dated June 7, 2018 in view of Vanda decision. This Memorandum stated that the Federal Circuit's decision in Vanda illustrates several important points regarding the subject matter eligibility analysis.
"First, the Federal Circuit evaluated the claims as a whole, including the arguably conventional genotyping and treatment steps, when determining that the claim was not "directed to" the recited natural relationship between the patient's genotype and the risk of QTc prolongation. The importance of evaluating the claims as a whole in Step 2A was also emphasized by the Federal Circuit in previous cases, such as Finjan Inc. v. Blue Coat Systems, Inc., 879 F.3d 1299 (Fed. Cir. 2018), and Core Wireless Licensing S.A.R.L., v. LG Electronics, Inc., 880 F.3d 1356 (Fed. Cir. 2018). The two prior cases are discussed in a memorandum dated April 2, 2018 to examiners titled "Recent Subject Matter Eligibility Decisions."
Second, the Federal Circuit cited the Supreme Court "[t]o further underscore the distinction between method of treatment claims and those in Mayo." Id. at 113 5. Method of treatment claims (which apply natural relationships as opposed to being "directed to" them) were identified by the Supreme Court as not being implicated by its decisions in Mayo and Myriad because they "confine their reach to particular applications." Id. The Federal Circuit noted that while the "claim in Mayo recited administering a thiopurine drug to a patient, the claim as a whole was not directed to the application of a drug to treat a particular disease." Id. at 1134. That is, while the Mayo claims recited a step of administering a drug to a patient, that step was performed in order to gather data about the natural relationships, and thus was ancillary to the overall diagnostic focus of the claims. The Mayo claims were not "method of treatment" claims that practically apply a natural relationship.
Lastly, the Federal Circuit did not consider whether or not the treatment steps were routine or conventional when making its "directed to" determination. Since the claim was determined eligible in the step 2A "directed to" part of the test, there was no need to conduct a step 2B analysis."
The quickness with USPTO reacted to the findings and rulings in Vanda demonstrate the dynamic approach of the Patent office to deal and resolve the question related to patent eligible subject matter.
Indian law position on PMT: time to change?
It is right time to review the doctrine of patent non-eligibility under section 3 (i) which excludes certain innovations from patent protection based on the recommendations of Justice Ayyanger report 1959.
"(e) Processes for medicinal, surgical, curative, prophylactic and other treatment of man and processes for similar treatment of animals or plants to render them free of disease or to increase their economic value or that of their products."
"332. As regards para (e) inventions of medicinal or surgical treatment of man are universally not patentable. Similarly curative processes for the treatment of plants or animals have been held not to be "a manner of new manufacture" and therefore not patentable in the U.K. (vide Rau's application, 52 RPC 362—production of lupin seeds of high oil content); in the matter of American Chemical Paint Coy's Application,1 (treatment of cotton plants). In the matter of an application by the Canterbury Agricultural College (treatment of sheep for increasing the wool yield). It appears therefore that this type of invention is unpatentable in India also under the Indian Patents and Designs Act, 1911 when the statute uses the same words "manner of new manufacture". To avoid doubt and clarify the law, I have included the inventions specified in paragraphs (d) and (e) in the first sub-clause—which has retrospective effect."
Notes on clauses
Clause 3.—This clause specifies what is not 'patentable' and is based upon judicial decisions on the subject.
When same clause 3 was kept in the Patent Bill 62 f 1965 with minor amendment by insertion of word "any" before the exiting clause 3 "Processes for medicinal, surgical, curative, prophylactic and other treatment of man and processes for similar treatment of animals or plants to render them free of disease or to increase their economic value or that of their products." , the justification in the notes of clauses remained martially same as stated earlier but the purpose to codify this provision was attributed to non- availability of case law on the subject in India.
Notes on clauses : Patent Bill 62 of 1965
Clause 3.- In this clause are set out several types of inventions or alleged inventions which are regarded universally or almost universally as not being patentable. In view of non- availability of case law on the subject in India, it would be advantageous to codify this part of law as generally under stood and applied.
If we see notes on clauses on this clause 3 we will find that this position was codified to account for the "inventions which are regarded universally or almost universally as not being patentable" at that point of time. More so it was also acknowledged that "In view of non- availability of case law on the subject in India, it would be advantageous to codify this part of law as generally under stood and applied." This provision remained active till 2002 as section 3 (i) in the finally passed Patent Act, 1970 and this position was amended in 2002 by Act of 38 of 2002 when words '[ diagnostic, therapeutic ] ' were added in this section and the application of this clause to plants was removed by deletion of words '[or plant ]'' in view TRIPS agreement. The position before 2002 was that the process for diagnostic or therapeutic was available for patent grant provided it satisfies other conditions of patentability. Most of the diagnostic and therapeutic processes were denied patent in India before 2002 as such processes were not treated as manner of manufacture or deemed to lack industrial applicability. Position after the amendment still remained in flux for the patent applications relating to the process for diagnostic or therapeutic application. Though the applicant is not under obligation to state all the intended uses of the invention but pre-condition of industrial applicability under section 2(1) (j) perhaps puts a road block to patentability of such inventions in India.
Inclusion of "diagnostic or therapeutic" for exclusion
The 2002 amendments in section 3 (i) added more categories of subject matter for exclusions as 'inventions not patentable' though allowed such processes for treatment of plants. Without clearly defining the ambit of terms 'diagnostic or therapeutic' the patent law left the discretion of the IPO to interpret these terms. The position of the judicial precedence remained the same as stated by Justice Ayyanger. There is still a non- availability of case law on this subject matter of exclusion in India. The question of patent protection for methods of 'medical treatment' which covers therapeutic methods, diagnostic methods and surgical methods remained in debate and resolved in different manner in US, Europe and UK. But all the patent jurisdictions agreed by Article 27(3)(a) of TRIPS agreement to allow the members to exclude from patent protection the diagnostic ,therapeutic and surgical methods for treatment of humans or animals. Since members agreed to keep this provision open ended the word "may" was used in the article 27(3)(a). So whether the member excludes or not, there would be compliance with the TRIPS agreement.
Manual of Indian patent practice
Since the definition of term 'Therapy' remained elusive in absence of any Indian judicial pronouncement the manual of the patent office practice relied on the case law of other jurisdictions to interpret the term 'therapy' and also applied the case law ruling in the other jurisdictions.
"The term "therapy'' includes prevention as well as treatment or cure of disease.
Therefore, the process relating to therapy is also not patentable as held in Unilever Limited (Davis') Application,  RPC 219. Although some medical dictionaries pointed towards a narrow interpretation of the term, other works of reference, including non-specialist dictionaries, indicated a more general meaning; this was preferred in this case, following the principle that words in statutes dealing with matters relating to the general public are presumed to be used in their popular, rather than their narrowly legal or technical, sense. However, for a treatment to constitute therapy, there must be a direct link between the treatment and disease state being cured, prevented or alleviated, (BL O/248/04). It appears that any medical treatment of a disease, ailment, injury or disability, i.e., anything that is wrong with a patient and for which he would consult a doctor, as well as prophylactic treatments such as vaccination and inoculation, is to be regarded as therapy. The same considerations apply for animals as for human patients, so that for example prophylaxis and immunotherapy in animals are regarded as therapy [T 24/91]."
Time to review the IPO guidelines on 'medical treatment'
When section 3(i) exclusion was introduced in 1970 it was done to follow the judicial precedence elsewhere. Essentially the whole subject matter of medical treatment was conceived as non-economic with no industrial application. However, we must examine these provisions afresh to accommodate and determine to what extent section 3(i) limit the patenting of new treatments such as genetic therapy, stem cell therapy and genetic diagnostic testing. These guidelines do not provide much assistant to IPO in dealing with cases involving application of natural relationship where claims are directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome.
The issue of patentability of PMT has undergone many changes since the 'Canavan gene patent controversy' in early 1980 which raised some pertinent issue relating to ownership of gene and the recent Vanda case opened up the possibility of patenting such patent claims. Is it not the right time for IPO to revise its guidelines to accommodate such promising patents in the list of eligible patents? One must realise that developing diagnostic methods particularly the customised ones is not only costly but also time consuming. We may or may not find Dan Greenberg type of initiative again to find 'Canavan gene' but opening up patent protection for such technologies could be an encouraging step in securing RD investment in this promising field of Personalised Medical treatment.
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