The Supreme Court in Mayo Collaborative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289, 1294, 1296-98 (2012) requires application of a two-part test for determining patent eligibility under section 101. First, one must ask whether the patent is directed to one of the patent-ineligible concepts. If the answer is no, the inquiry is over: the claim falls within the ambit of section 101. Second, if the answer is yes, one must still determine whether, considered both individually and as an ordered combination, the additional elements transform the nature of the claim into a patent-eligible application. Step two is oftn described “as a search for an inventive concept”. At step two, more is required than “well-understood, routin, conventional activity already engaged in by the scientific community”. 

The Federal Circuit in Rapid Litigation Management v. Cellzdirect, Inc., (2016) points to the importance of step one in the inquiry above. In this case, the district court granted summary judgment that US patent 7,604,929 was invalid under 35 USC 101 as being directed to a patent ineligible law of nature –that hepatocytes are capable of surviving multiple freeze thaw cycles. Hepatocytes are a type of liver cell with a number of uses such as in the testing and diagnostic field. Prior to the patent, scientists frooze hepatocytes and then when needed, thawed them and recvoered the viable cells using density gradient fractionation. Applicant’s of the ‘929 patent discovered that one could actually freeze the hepatocytes twice and still obtain viable cells. Using this knowledge, the applicant’s developed a process of preserving hepatocytes and patented a claim for a process that comprised a number of steps such as subjecting previously frozen and thawed cells to density gradient fractionation to separate viable cells from non-viable ones, recoveirng the viable cells and refreezing the viable cells. 

The Federal Circuit reversed the district court’s decicion on the basis that contrary to being directed to a “natural law” which was the cells capability of surviving multiple feeze thaw cycles, the claims were clearly directed to a new and useful laboratory technique for preserving hepatocytes. This type of process, carried out by an artisan to achieve “a new and useful end” is precisely the type of claim that is eligible for patenting. (citing Alice Corp. v. CLS Bank Int’l, 134 S. Ct. 2347, 2355 (2014). The Court noted that while the inventors certainly discovered the cells’ ability to surive multiple feezing thaw cycles, that is not wehre they stopped, nor is what they patented. Rather, “as the first party with knowledge of” the cells’ ability, they were “in an excellent position to claim applications of that knowledge.” (citing Myriad, 133 S. Ct. 15 2120). The end result of the ‘929 patent claims was not simply an observation or detection of the ability of hepatocytes to survive multiple feeze thaw cycles. Rather, the claims are directed to a new and useful method of preserving hepatocyte cells. 

Also of interest in this case is a nice contrast to other important cases where the hurdles of 101 were not met because they amounted to nothing more than observing or identifying the ineligible concept itself.. 

Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1373-74 (Fed. Cir. 2015), cert. denied, No. 15-1102, 2016 (WL 1117246 (June 27, 2016). The existence and location of cffDNA is a natural phenomenon; identifying its presence was merely claiming the natural phenomena itself. The Court determined that the claims were “directed to” the patent ineligible cffDNA itself. 

Genetic Techs., Ltd. v. Merial L.L.C., 818 F.3d at 1369, 1373-74 (Fed. Cir. 2016): In this case the claim recited methods for detecting a coding region of DNA based on its relationship to non-coding regions. Becasue the relationship between coding and non-coding sequences was a law of nature, the claim amounted to nother other than identifying “information about a patient’s natrual genetic makeup.” 

In re CRCA1- & CRCA2-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 761-62 (Fed. Cir. 2014): The case recited methods for screening human germline for an altered BRCA1 gene by comparing the target DNA sequence with wild-type sequence. Comparing two sequences to detect alterations is a patent ineligible “abstract mental process” 

Of further note with the Rapid litigation case, the Court stated that even if the ‘929 patent is “directed to ” hepatocytes’ natural ability to survive multiple feeze thaw cycles, the Court would find the claims patent eligible at the second step of the analysis as having transformed the process into an inventive application of the patent ineligible concept because the claims recited an improved process for preserving hepatocytes for later use. The benefits of the imporved process over the prior art methods are significant because they applied the discovery that hepatocytes can be twice frozen to acheive a new and useful presrvation process. (citing Mayo, 132 S. Ct at 1293-94 “An application of a law of nature or mathematical formula to a known structure or process may well be deserving of patent protection”, quoting Diehr, 450 US at 187. While each of the claims’ individual steps (freezing, thawing, and seaprating) were known independently in the art also did not make the claim unpatentable. Instead, one must view the claim as a whole, considering their elements both individually and “as an ordered combination” (citing Alice, 134s S. Ct. at 2355, quoting Mayo 132 S. Ct. at 1298). While the individual steps of feezing and thawing were well known, a process of preserving hepatocytes by repeating those steps was itself far from routine and conventional becasue the prior art only disclosed methods having one feeze thaw cycle of hepatocytes, wehrein upon thawing, a gradient centrifugation step is required to remove the non-viable cells. Repeating a step that the art taught should be performed only once can hardly be considered routine or conventional. 

The claims for example 30 from the May USPTO life science examples re below. By way of background, the “Texas mint” plant as a thin liquid sap containing about 10% texiol, water and other nutrients. Texiol is lower in calories and tastes sweeter than table sugar, but it has a bitter aftertaste. Applicant discloses that trained sensory panels reviewed the formulations having varying concentrations of texiol in water, and preferred dietary sweetener comprising 1-5% texiol and at least 90% water. Applicant also discloses a dietary sweetener comprising texiol mixed with water and Compound N which is a natural flavor exccreted from mushrooms and having a mild umami taste. When combined with texiol in particular amounts, compound N neutralizes the bitter aftertaste of texiol, even though it does not chemically react with texiol. The sensory panel found that a formulation having 1-5% texiol, 1-2% compound N and the balance water produced the best results with no bitter aftertaste. Applicant also found that upon tasting naturally occurring texiol, the sensory panel reported perceiving an immediate bust of sweetness that rapidly dissipated. Because prolonged sweetining is desireable, applicant discloses dietary sweeteners haivng texiol in a controlled release formulation. 

2. A dietary sweetener comprising:

1-5 percent texiol; and  at least 90 percent water. 

3. A dietary sweetener comprising:

1-5 percent texiol; and at least 90 percent water; and 1-2 percent Compound N. 

6. A dietary sweetner comprising:

texiol in a controlled release formulation. 

The broadest reasonable interpretation of claim 2 does not encompass the naturally occurring sap of the Texas mint plant, which contains a different amount of texiol (10%). But the claim falls within the natural product exeption because texiol and water are composed of matter and thus the claim is drawn to a composition of matter and although the combination as claimed is novel and does not occur in nature, there is no indication that mixxing 1-5 percent texiol with at least 90% water changes the structure, funciton, or other properties of the texiol or water in any marked way. The claim also does not add significantly more than the exeption, either individually or as a combination in that each component continues to ahve the same properties in the mixture as it had alone and mixing sweeters with water was well-understood, routine, conventional activity engaged in by those in the filed prior to applicant’s invention. 

Claim 3 is still drawn to a composition of matter. But when the claimed mixture is compared to its counterparts in nature, the mixure has a changed property of taste. It is thus not a “product of nature” exception. 

Claim 6 is still drawn to a composition of matter. However, the claimed formulation which is compared to its counterpart (naturally occurring texiol in its natural state) has altered time release properties which constitute marked difference in characteristics. It is thus not a “product of nature” exception. 

The seven claims presented in example 29 are as below. According to the example, all but claim 2 are considered to be patent eligible. A couple things via way of background in the example. “Julitis? is an autoimmune disease that casues chronic inflammation and an itchy and extremely painful rash on the fact hands, and feet. Applicant discovered that the presence of the “JUL-1” protein in a person’s plasma is indicative that the person has julitis. Applicant’s immunoassays use human or porcine anti-JUL-1 antibodies. Prior to the invention, the use of porcine antibodies in veterinary therpauetics was known in the filed, but these antibodies were not routeinly or conventionally used to detect human proteins such as JUL-1. Prior to the invention, julitis was also conventionally treated with anti-tumor necrosis factor (TNF) antibodies. Julitis patients were also often misdiagnosed as having rosacea because the rash caused by julitis looks similar to rashes caused by roacea and such patients would be given rasacea treatments such as antiboditics. Applicant’s diagnostic methods improved patient outcomes by ensuring that patients who have julitis would be accurately diagnosed due to detecting JUL-1 in their plasma and then properly treated with anti-TNF. 

1.  A method of detecting JUL-1 in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient; and
    b.  detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody and detecting binding between JUL-1 and the antibody.

2.  A method of diagnosing julitis in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient;
    b.  detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody and detecting binding between JUL-1 and the antibody; and
    c.  diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.

3.  A method of diagnosing julitis in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient;
    b.  detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with a porcine anti-JUL-1 antibody and detecting binding between JUL-1 and the porcine antibody; and
    c.  diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.

4.  A method of diagnosing julitis in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient;
    b.  detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with antibody mAb-D33 and detecting binding between JUL-1 and antibody mAb-D33; and
    c.  diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.

5.  A method of diagnosing and treating julitis in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient;
    b.  detecting whether JUL-1 is present in the plasma sample;
    c.  diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected; and
    d.  administering an effective amount of topical vitamin D to the diagnosed patient.

6.  A method of diagnosing and treating julitis in a patient, said method comprising:
    a.  obtaining a plasma sample from a human patient;
    b.  detecting whether JUL-1 is present in the plasma sample;
    c.  diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected; and
    d.  administering an effective amount of anti-tumor necrosis factor (TNF) antibodies to the diagnosed patient.

7.  A method of treating a patient with julitis, the method comprising administering an effective amount of anti-TNF antibodies to a patient suffering from julitis.

Claim 1 is eligible because steps (a) and (b) of the claim “do not recite or describe any recognized exception” (the example cites Mayo Collaborative Services v. Prometheus Laboratories, Inc. in support of this determination, which the example indicates stands for the proposition that the recited steps of administering a drug to a patient and determining the resultant level of 6-thioguanine in the patient “are not themselves natural laws”).  As a result, the analysis of this claim ends with Step 2A of analytic framework set forth in the Interim Guidance (i.e., determining whether the claim is directed to a judicial exception), and the example notes that there is no need to proceed with Step 2B of the analytic framework (i.e., determining whether any element, or combination of elements, in the claim is sufficient to ensure that the claim amounts to significantly more than the judicial exception).

With respect to claim 2, the example explains that:

[T]he claim recites diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected, which describes a correlation or relationship between the presence of JUL-1 in a patient’s plasma and the presence of julitis in the patient.  This limitation sets forth a judicial exception, because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by the Supreme Court in Mayo).  Additionally, step c could be performed by a human using mental steps or basic critical thinking, which are types of activities that have been found by the courts to represent abstract ideas (e.g., the mental comparison in Ambry Genetics, or the diagnosing an abnormal condition by performing clinical tests and thinking about the results in Grams).

As a result, claim 2 is found to be directed to “at least one exception.”  As for Step 2B of the analytic framework, the example explains that the claim’s step of “[o]btaining a sample in order to perform tests is well-understood, routine and conventional activity for those in the field of diagnostics,” and that the claim’s step of “[d]etecting whether JUL-1 is present in the plasma sample merely instructs a scientist to use any detection technique with any generic anti-JUL-1 antibody,” and further, that:

When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well-understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting a protein using an antibody to that protein. 

According to the example, consideration of the additional elements as a combination does not save claim 2 because “[u]nlike the eligible claim in Diehrin which the elements limiting the exception are individually conventional, but taken together act in concert to improve a technical field, the claim does not invoke any of the considerations that courts have identified as providing significantly more than an exception.”  Finding that claim 2 claim as a whole does not amount to significantly more than the exception itself, the Office determines that this claim is not eligible.

Claim 3, differs from claim 2 in that the detecting step utilizes a porcine anti-JUL-1 antibody, which is eligible because:

[A]t the time the application was filed, the use of porcine antibodies in veterinary therapeutics was known to most scientists in the field.  But significantly, there is no evidence that porcine antibodies were routinely or conventionally used to detect human proteins such as JUL-1.  Thus, the claim’s recitation of detecting JUL-1 using a porcine antibody is an unconventional step that is more than a mere instruction to “apply” the correlation and critical thinking step (the exception) using well-understood, routine or conventional techniques in the field.

Similarly, claim 4, which differs from claims 2 and 3 in that the antibody mAb-D33 is utilized in the detecting step, is found to be eligible because:

[A]t the time the application was filed, antibody mAb-D33 was not routinely or conventionally used to detect human proteins such as JUL-1.  Thus, the claim’s recitation of detecting JUL-1 using mAb-D33 is an unconventional step that is more than a mere instruction to “apply” the correlation and critical thinking step (the exception) using well-understood, routine or conventional techniques in the field.

Claim 5 also differs from claim 2 in that claim 5 is directed to a method of diagnosing and treating julitis, the detecting step of claim 5 encompasses any technique for detecting whether JUL-1 is present in the plasma sample, and claim 5 adds an additional step of administering an effective amount of topical vitamin D to the diagnosed patient.  Unlike claim 2, however, the example finds claim 5 to be eligible.  The example explains that claim 5 is eligible because:

[T]his claim further recites an additional element of administering an effective amount of topical vitamin D to the diagnosed patient (step d).  Vitamin D was known to doctors, and was routinely and conventionally used as an oral supplement to maintain bone health prior to applicant’s invention, and at the time the application was filed.  However, mere knowledge of vitamin D or its use in other ways to treat other medical conditions does not make the administration of topical vitamin D to treat julitis a conventional step that those in this field would routinely practice.  The evaluation turns on whether the use of topical vitamin D was widely prevalent in the field at the time the invention was made and the application was filed.  Because it was not, the recitation of administering topical vitamin D is an unconventional step that is more than a mere instruction to “apply” the correlation and critical thinking step (the exception) using well-understood, routine or conventional techniques in the field.

Claim 6, which differs from claim 5 in that an effective amount of anti-tumor necrosis factor (TNF) antibodies –- rather than an effective amount of topical vitamin D –- is administered to the diagnosed patient, is also found to be eligible in example 29.  Although the example explains in analyzing claim 6 that “[p]rior to applicant’s invention, and at the time the application was filed, julitis was conventionally treated with anti-tumor necrosis factor (TNF) antibodies, but for unknown reasons, some patients do not respond well to this conventional treatment,” the example states that:

When the additional elements are viewed as a combination, however, the additional elements (steps a, b and d) amount to a claim as a whole that adds meaningful limits on the use of the exception (the correlation and critical thinking step).  The totality of these steps including the recitation of a particular treatment (administration of an effective amount of anti-TNF antibodies) in step d integrate the exception into the diagnostic and treatment process, and amount to more than merely diagnosing a patient with julitis and instructing a doctor to generically “treat it.”  Further, the combination of steps, which is not routine and conventional, ensures that patients who have julitis will be accurately diagnosed (due to the detection of JUL-1 in their plasma) and properly treated with anti-TNF antibodies, as opposed to being misdiagnosed as having rosacea as was previously commonplace.  See Diamond v. Diehr, 450 U.S. 175, 188 (1981) (“a new combination of steps in a process may be patentable even though all the constituents of the combination were well known and in common use before the combination was made”).

Claim 7, which is directed to treating a patient with julitis by administering an effective amount of anti-TNF antibodies to the patient, is eligible, because “[t]he recited step of administering antibodies to a patient suffering from julitis does not recite or describe any recognized exception” (the example again cites Mayo Collaborative Services v. Prometheus Laboratories, Inc. in support of this determination, which the example indicates stands for the proposition that the recited steps of administering a drug to a patient and determining the resultant level of 6-thioguanine in the patient “are not themselves natural laws”).  As with claim 1, the analysis of claim 7 ends with Step 2A of analytic framework, and the example notes that there is no need to proceed with Step 2B.

The USPTO has put out some helpful examples for the life sciences which can be found at http://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf  

The examples should be used in conjunction with the 2014 Interim Guidance on Subject Matter Eligibility.

To give you just a flavor for the examples, the PTO has a section on vaccines and how one goes about the analysis for nature based products..

One example is the following. “1. A vaccine comprising live attenuated Pigeon flu virus”.

The live attenuated virus is a nature-based product that must be compared to its naturally occurring counterpart. In this instance, the closest natural counterpart is the naturally occurring Pigeon flue virus from which the live attenuated virus was mutated. Since no mutations of this gene are known to occur in nature, under the holding in Myriad, this structural difference is a markedly different characteristic, because it causes the claimed virus to have a nucleotide sequence that is different from anything found in nature.

But contrast this to the next claim:

“2. A vaccine comprising: Peptide F; and a pharmaceutically acceptable carrier”.

In this case, assume that peptide F is a naturally occurring peptide produced by the Piegeon flu virus. Here again, the recited mixture of Peptide F and water is a nature baed product that must be compared to its closest naturally occurring counterpart. Because peptide F and water do not occur together in nature, there is no naturally occurring counterpart mixture for comparison, and so the claimed mixture is compared to its naturally occurring compoents, i.e., peptide F and water. Peptide F is naturally occurring and water is naturally occurring so neither would be eligible as claimed on their own. While the mixture is novel and does not occur in nature, there is no indication that mixing these components changes the structure, function, or other properties of the peptide or water. The calimed mixture as a whole does not display markedly different characteristics compared to the naturally occurring counterparts. Accordingly, each components is a “product of nature” judicial exception. Next, the claim as a whole is analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Mixing the peptide with a carrier such as water does not markedly change the characteristics of either component, because each component continues to have the same properties in the mixture as it had alone. In addition, using a carrier in a peptide vaccine was well-understood, routine & conventional prior to the invention and at the time of filing the application, so the mixing of the peptide and carrier, when recited at this high level of generality, does not meaningfully limit the claim. Thus, the claim as a whole does not amount to significantly more than each product of nature” by itself and does not qualify as eligible subject matter.

But suppose the claim recited “A vaccine comprising: peptide F; and a pharmaceutically acceptable carrier selected form the group consisting of a cream, emulsion, gel, liposome, nanoparticle, or ointment”. Here, the claimed cream for example, has different structural and physical characteristics than its naturally occurring components. For example, oil droplets are small, uniform in size, and homogenously dispersed in the water, which causes the resultant cream to have a semi-solid and non-flowable form at room temperature as compared to just oil and water, which are both flowable liquids at room temperature in nature. The cream’s changed form and adherence are marked differences in structural and physical characteristics as compared to the natural counterparts, and thus the cream is not a “product of nature” exception. One would not even need to go to the step of determining whether any additional element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. There is no exception in this case. 

The PTO has another interesting section on diagnostic claims.

Suppose that you discover the presence of a protein known as “UL-1” in a persons body that is indicative that the person has julitis. You first claim s the following:

“1. A method of detecting UL-1 in a patient, said method comprising: obtaining a plasma sample form a human patient; and b. detecting whether UL-1 is present in the plasma sample by contacting the plasma sample with an anti-UL-1 antibody and detecting binding between UL-1 and the antibody.” 

Your second claim is the following:

“2. A method of diagnosing julitis in a patient, said method comprising: a. obtaining a plasma sample from a human patient; b. detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with a porcine anti-JUL-1 antibody and detecting binding between JUL-1 and the procaine antibody; and c. diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected.” 

The first claim is eligible and the second is ineligible. But the second claim is actually eligible! . Both of the claims are directed to a process, which is one of the statutory categories of invention. However, claim 1 is not directed to any judicial exception. It differs from Mayo above in that the claim only recites steps of obtaining a plasma sample from a patient and detecting whether JUL-1 is present in the plasma sample by contacting the plasma sample with an anti-JUL-1 antibody. This is different from claim 2 which is directed to making a correlation or relationship between the presence of JUL-1 in a patient’s plasma and the presence of julitis in the patient. This limitation sets forth a judicial exception because this type of correlation is a consequence of natural processes, similar to the naturally occurring correlation found to be a law of nature by Mayo above. This additional step could be performed by a human using mental steps which are activities that have been found to constitute abstract ideas, which is a judicial exception (they may alternatively be called “law of nature”). So for claim 2, you would need to move on with the analysis and ask whether any element, or combination of elements, is sufficient to ensure that the claim amounts to significantly more than the exception. Obtaining a sample in order to perform tests is well-understood and detecting whether JUL-1 is present in the plasma sample merely instructs a scientist to use any detection technique with any generic anti-JUL-1 antibody. This claim would not withstand challenge. 

The above is just a flavor and one should look at the examples. However, what strikes me most about the above is the strange consequence of Mayo analysis where claim 2 actually recites more than claim 1, albeit the judicial exeption which is the so called abstract idea of making a comparison, above but is itself found ineligible over claim 1. 

The Disctrict Court for the District of Delaware in Endo Pharmaceuticals Inc. v. Actavis Ind (D. Del. 2015) casts doubt as to whether the 2011 Federal Circuit case of Classen discussed earlier in this Blog has any precedential value in light of Mayo. In particular, the Court dismissed the argument that a mandatory application step is sufficiently transformative so as to save claims which are otherwise unpatentable under 35 USC 101. As stated in Mayo, one must do more than simply state the law of nature while adding the words “apply it”. 

The claims in issue had a step (c) “orally administering to said patient, in dependence on which creatinine clearance rate is found, a lower dosage of the dosage form to provide pain relief”

1. A method of treating pain in a renally impaired patient, comprising the steps of:

a. providing a solid oral controlled release dosage form, comprising:

i. about 5 mg ot about 80 mg of oxymorphone or a pharmaceutically acceptable sale thereof as the sole active ingredient; and

ii. a controlled release matrix;

b. measuring a creatinine clearance rate of the patient and determining it to be (a) less than aobut 30 m [L]/min, (b) aobut 30 mL/min to about 50 mL/min, (c) about 51 mL/min to about 80 mL/min, or (d) above about 80 mL/min; and

c. orally adminsitering to said patient, in dependence on which creatnine clearance rate is found, a lower dosage of the dosage form to provide pain relief;

wherein after said administration to said patient, the average AUC of oxymorphone over a 12-hour period is less than about 21 ng-hr/mL.