FDA Releases Stem Cell Guidance Documents

Therapies that use autologous or allogeneic stem cells are examples of early personalized therapies. Removing cells from a patient and reintroducing them to the same or a matched patient, for example, as done in bone marrow transplants or peripheral blood stem cell transplantation, has provided benefits to many patients and are effective treatments for leukemia, lymphoma, myelodysplasia, multiple myeloma, and certain immune deficiency diseases. Continue reading this entry

FDA Approves Companion Dx for PD-1 Inhibitor

According to the American Cancer Society (“ACS”), lung cancer (both small cell and non-small cell) is the second most common cancer in both men and women (not counting skin cancer). About 14% of all new cancers are lung cancers and 85 % of those are non-small cell lung cancers (NSCLCs). Continue reading this entry

USPTO Update on Patent-Eligibility for Life Science Inventions

On August 2nd 2017, the USPTO hosted a Bicoastal Biotechnology/Chemical/Pharmaceutical Customer Partnership that focused on the USPTO’s current thinking on patent-eligibility. The meeting followed the USPTO’s June 25th, 2017 publication of its report “Patent Eligible Subject Matter: Report on Views and Recommendations from the Public” (“Report”) which summarized the case law, international approaches to defining patent eligible subject matter and the public’s view on patent-eligible subject matter.

Subject Matter Eligibility From the USPTO’s Perspective

Dr. Daniel Kolker, Supervisory Patent Examiner, TC 1600, summarized trends in Section 101 examination, claiming strategies, and successful arguments to avoid or overcome a Section 101 rejection. From the USPTO’s perspective, the PTO’s December 2014 Interim Guidance is the controlling resource document for the pubic and PTO examiners.

The Guidance set forth the Alice/Mayo two-part test for determining patent eligibility:

Step 1:     Is the claim drawn to one of the four statutory categories of eligible subject matter?

Step 2A:  Is the claim directed to a judicial exception?

Step 2B:  If the answer to Step 2A is yes, then do the claim elements add significantly more to the judicial exception?

Based on this analysis, Dr. Kolker explained that based on the Alice/Mayo two-part test, applicants have two options for establishing eligibility: drafting a claim that does not recite a judicial exception, or if the claim does recite a judicial exception, reciting claim elements that add “something more” to the judicial exception.

Claiming Diagnostic Inventions

Diagnostic method claims in personalized medicine often recite a judicial exception because the claims typically correlate the presence or absence of a biological marker or clinical measurement to a diagnosis, prognosis or preferred treatment. Thus, for claims that recite an abstract idea or natural phenomenon (the correlation step), removing the element defining the correlation or abstract idea from the claims will take the claim out of the recitation of the judicial exception and preclude a rejection for lack of patent-eligibility. Thus, the claim may now be directed to a method of detecting a marker of significance, without the ultimate correlation to the diagnosis, disease or preferred treatment. In some instances, this option is not possible due to prior art that discloses detection of the marker, especially in the patient population.

Where the claim must recite a judicial exception, a case why the claim elements, individually or in combination, add significantly more to the judicial exception (Step 2B) must be made. Examiners may reject the additional elements in the claim as not “something more” because they are routine and conventional in the art. However, such assertions must be substantiated by the examiner, typically by citing a technical publication. Patent applicants may rebut this evidence by providing contrary evidence, perhaps by way of declaratory statement by an expert in the relevant art, that the additional elements are not in fact routine and conventional.

For multivariate diagnostic methods, the “something more” could be established if the combination of markers provides a different or more precise diagnosis that could be established by the use of a single marker alone. In addition or alternatively, the method itself might utilize steps or techniques that are not routinely combined, to provide an enhanced or novel outcome.

In addition, when the method directs a physician to select a therapy or treatment option, the addition of the treatment step to the claim may be a strategy to overcome a lack of patent-eligibility rejection, provided the treatment itself is not too generic.

Products of Nature

Natural products, for example isolated nucleic acids, proteins and stem cells, provide significant challenges under the new guidelines, as the therapeutic value of many of these inventions lies in its similarity to a natural product. Under the 2-part analysis, patent-eligibility can be established if there are features or characteristics that distinguish the claimed product from its natural counterpart. A possible strategy is to add new claim elements that provide features that distinguish the claimed invention from the natural product. For example, claiming the product as a composition that contains additional elements such as preservatives or stabilizers can provide the claimed product with distinguishing characteristics or features. For example, the addition of additional peptides to a protein or peptide fragment may enhance solubility or cell penetration, and thus may provide the markedly different characteristics to establish the combination as patent-eligible.

The New Reality

There is no doubt that obtaining patent protection for life science inventions is more challenging in light of the US Supreme Court’s recent 101 jurisprudence. However, that is not to say that patenting is precluded. The preceding strategies as suggested by the USPTO provide useful avenues to move beyond the current challenges.

 

Why The Federal Circuit Revisited Written Description

In Stanford University v. The Chinese University of Hong Kong (Fed Cir. No 2015-2011, June 27, 2017), the Federal Circuit vacated and remanded interference decisions on the ground the Patent Trial and Appeal Board (“Board”) applied the incorrect standard in determining whether a patent specification satisfies the written description requirement. The decision is interesting because it is yet another review of patents related to prenatal detection of fetal DNA, and because the Federal Circuit addressed when post-filing evidence can be used to establish possession of a claimed invention.

The Claimed Technology – Detecting Fetal Aneuploidies

The claimed technology relates to “testing methods for fetal aneuploidies, conditions in which a fetus either has an abnormally high number of chromosomes (e.g., Down’s syndrome, a result of trisomy 21) or an abnormally low number of chromosomes (e.g., Turner’s syndrome, a result of a missing copy of an X chromosome).” Slip Op. at 2-3. Stanford professor Stephen Quake and Chinese University of Hong Kong professor Dennis Lo both developed methods that relied on detecting cell-free fetal DNA (“cff-DNA”) present in maternal blood in small amounts. A technical challenge in detecting cff-DNA in a maternal blood sample is distinguishing the maternal DNA from fetal DNA.

Quake developed a technique to account for the interfering maternal DNA. His technique relied on a “digital analysis” method to detect small changes in the quantity of an aneuploid chromosome relative to one or more normal chromosomes, without distinguishing between maternal and fetal DNA. Quake’s U.S. Patent No. 8,008,018 (‘018 patent) describes the technique as involving the “separation of extracted genomic material into discrete units so that the detection of a target sequence (e.g., chromosome 21) may be simply quantified as binary (0,1) or simple multitudes, 2, 3, etc.” Slip Op. at 3, citing col. 1, lines 49-52 of the ‘018 patent.

Quake’s digital analysis method requires a large number of samples because only a small amount of cff-DNA is present in the maternal sample. The ‘018 patent notes that the digital PCR technique, which uses target-specific primers, is the preferred method for amplifying and detecting target sequences. Slip Op. at 4. The patent also discloses that second generation massively parallel sequencing (“MPS”) can perform Quake’s method using, for example, Illumina’s sequencing platform that was disclosed in the patent specification as a means to carry out the method.

Lo’s method to account for interfering maternal DNA relies on a random sequencing method that uses random MPS. Random MPS does not require the detection of specific target sequences; rather, DNA present in the maternal sample is sequenced using random MPS and the sequenced fragments are aligned to a reference genome to determine a chromosomal region of origin for each sequence. After the sequences are mapped to the chromosome, the numbers of mapped sequences are compared. A disproportionate number of aligned sequences to chromosome 21 is indicative of Down’s syndrome trisomy. Lo filed a patent application describing the random sequencing method.

Quake’s first patent (which issued as U.S. Patent No. 7,888,017) claimed the targeted method to analyze cff-DNA. Quake filed a continuation application which ultimately issued as the ‘018 patent. Quake’s ‘018 patent claimed a method that randomly sequenced DNA fragments. Claim 1 of the ’018 patent recites:

  1. A method for determining presence or absence of fetal aneuploidy in a maternal tissue sample comprising fetal and maternal genomic DNA, wherein the method comprises:

a. obtaining a mixture of fetal and maternal genomic DNA from said maternal tissue sample;

b. conducting massively parallel DNA sequencing of DNA fragments randomly selected from the mixture of fetal and maternal genomic DNA of step a) to determine the sequence of said DNA fragments;

c. identifying chromosomes to which the sequences obtained in step b) belong;

d. using the data of step c) to compare an amount of at least one first chromosome in said mixture of maternal and fetal genomic DNA to an amount of at least one second chromosome in said mixture of maternal and fetal genomic DNA, wherein said at least one first chromosome is presumed to be euploid in the fetus, wherein said at least one second chromosome is suspected to be aneuploid in the fetus, thereby determining the presence or absence of said fetal aneuploidy.

Slip Op. at 6, citing ‘018 patent, col. 22, lines 48-67 (emphasis added).

The Interference History

In 2011, Quake added for the first time, claims to methods that explicitly cover random MPS methods in an application that ultimately issued as the ‘018 patent. Both Quake and Lo requested interferences to determine who invented the random sequencing method, and when the method was invented. Slip Op. at 7. Three interferences were declared.

Lo attacked Quake’s ‘018 patent as unpatentable for lack of written description. Lo’s expert, Dr. Stacy Gabriel, alleged that Quake’s specification describes the digital analysis method and not the random sequencing method invented by Lo. Quake countered and pointed to language of the specification that he alleged disclosed every aspect needed to detect aneuploidy using random MPS.

The Board sided with Lo, finding that the ‘018 patent specification disclosed targeted and not random sequencing and that the “specification would not have indicated to one of ordinary skill in the art that Quake was in possession of the claimed MPS method.” Slip Op. at 8. The Board found Dr. Gabriel’s testimony persuasive that the ‘018 patent specification is directed to digital analysis of targeted sequences, and that “the language relied upon by Quake could have related to either random or targeted sequencing but that, because ‘the main focus of the Quake ‘018 patent [was] on diagnosing aneuploidy with digital PCR, those of skill would have understood the discussion of massively parallel sequencing to refer to sequencing targeted, predetermined portions of the DNA in a sample, not sequencing of random DNA.” Slip Op. at 8. The Board also determined that the specification’s reference to the Illumina platform could support random MPS and targeted sequencing.

Stanford and Dr. Quake appealed.

Written Description

The Federal Circuit reviewed the Board’s legal conclusions de novo. The court began by noting that:

“Substantial evidence supports a finding that the specification satisfies the written description requirement when ‘the essence of the original disclosure’ conveys the necessary information – ‘regardless of how it’ conveys such information, and even when the disclosures ‘words’ [a]re open to different interpretation[s].’”

Slip Op. at 13-14, citing In re Wright, 866 F.2d 422, 424-25 (Fed. Cir. 1989).

In this case, the Federal Circuit determined that the Board erred in evaluating the testimony offered by Lo’s expert, Dr. Gabriel. The court stated that both the Board and Dr. Gabriel did not cite any evidence of targeted or random sequencing on the Illumina platform, prior to Quake’s filing date. The evidence offered by Dr. Gabriel were two post-dated references that discussed the use of targeted sequencing methods. The Board did not, however, rely on this evidence in support of its decision. The other evidence offered by Dr. Gabriel related to sequencing on a Roche platform, not the Illumina platform cited in the ‘018 patent.

The court also determined that the Board applied the incorrect standard in evaluating the teachings of the ‘018 patent specification. As stated by the court, “the Board’s task was to determine whether the ‘018 patent’s written description discloses random MPS sequencing, as recited by the later-added claims, not whether the description does not preclude targeted MPS sequencing.” Slip Op. at 18.

As a result of the aforementioned errors, the court vacated the interference decisions and remanded to the Board to reconsider whether the Quake patents and applications satisfy the written description requirement by examining the record evidence to pre-filing evidence related to Illumina’s products. Any post-filing evidence can only be relied upon as far as they contain evidence of random MPS sequencing or Illumina products that existed as of the filing date. Slip Op. at 19.

In sum, the court instructed the Board to examine “whether a person of ordinary skill in the art would have understood that the ‘018 patent’s specification disclosed random MPS sequencing, as opposed to whether the specification did not preclude MPS sequencing.” Slip Op. at 20.

USPTO Extends Cancer Immunotherapy Pilot Program

On June 29th, 2016, the USPTO announced the Cancer Immunotherapy Pilot Program to allow expedited examination of patent applications that pertain to cancer immunotherapy. Under the Program and after proper petition, the USPTO has examined qualifying applications out of turn thereby expediting examination. The Program was implemented to support the National Cancer Moonshot and was scheduled to expire on June 28th, 2017. While only in effect for just less than one year, over 80 petitions for Program participation have been filed and 9 patents have been granted to date. On June 23rd, 2017, the USPTO announced that the Program is now extended until December 31, 2018.

To qualify for the fee-free program, the patent application must contain one or more claims to a method of treating cancer using immunotherapy. The Program is open to:

  • Any application that has not yet received a first Office Action;
  • Any application where the petition is filed with a Request for Continued Examination; or
  • Any application that is not under final rejection if the claimed therapy is the subject of an active Investigational New Drug (IND) application that has entered Phase II or Phase III (FDA) clinical trials.

Additional information and the appropriate forms can be found at this USPTO web address.

The USPTO also announced on June 23rd that it may further extend the Program (with or without modifications) or terminate it depending on feedback received, continued interest, and program effectiveness.