Identification of the factors that result in obviousness rulings for biotech patents

Abstract

To demonstrate the influence of the US Supreme Court’s KSR case, our analysis has shown that the ratio of obvious ruling increased from 0.42 to 0.62 after this case, whereas the ratio of non-obvious ruling decreased from 0.47 to 0.28. Therefore, without the rigid application of a “teaching, suggestion or motivation” test, the trends of obvious and non-obvious CAFC rulings significantly increased and decreased, respectively.

Based on this analysis, biotech inventors should contemplate the factors that have resulted in ruling of obviousness, which include claims that are too broad, the lack of secondary considerations, the reasonable expectation of success, and the reason or motivation to create a structure based on structural similarity. The presence of these factors most likely would result in the rejection of the claim during patent prosecution or the invalidation of the claim in patent litigation. Two immunotherapy and vaccine cases have applied these factors to overcome the obvious rejections.

Introduction

A claimed invention is obvious and thus unpatentable if the differences between the subject matter to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time that the invention was made to a person with an ordinary level skill in the field. The obviousness of an invention is therefore grounds for the rejection of a claim during patent prosecution or for the invalidation of the claim in litigation. Unlike the straightforward matter of determining the novelty of an invention, obviousness is subjective. Whether an invention is obvious is a question of law and is based on the underlying facts that are found to provide substantial evidence.^1,2 Consequently, the most significant portion of the work that is involved in patent prosecution or litigation is related to the argument that the application or patent in the suit is not obvious based on prior knowledge.

During patent prosecution, an examiner bears the initial burden of presenting a prima facie case of obviousness.³ The prima facie case is a procedural tool and requires that the examiner initially produce sufficient evidence to support a ruling of obviousness. When the examiner establishes a prima facie case of obviousness, the burden shifts to the applicant to provide rebuttal evidence or argument.⁴ Once the applicant submits the rebuttal evidence, the prima facie case dissolves and the examiner must consider all of the evidence to determine whether the obviousness rejection should stand. When the United States Court of Appeals for the Federal Circuit (CAFC) hears this type of case, the judges review the determination of obviousness and the fact findings for substantial evidence that a reasonable mind might accept as adequate to support the conclusion.⁴

During patent litigation, the accused infringer must prove the invalidity of the obviousness through clear and convincing evidence. The CAFC’s determination of obviousness is based on factual inquiries that include the scope and content of the prior art, the level of ordinary skill in the art, the differences between the claimed invention and the prior art, and objective evidence of nonobviousness.

Statistics of CAFC Rulings on Obviousness

Our previous study demonstrated that the trends for obvious and non-obvious rulings in terms of CAFC decisions increased and decreased, respectively⁵ without the rigid application of a “teaching, suggestion, or motivation” (TSM) test after the US Supreme Court’s KSR case⁶ which was decided on April 30, 2007. To identify the overall tendency of CAFC decisions, particularly in biotech-related cases, we reviewed every case that was decided by the CAFC from 2001 to April 2013 (Fig. 1), which included 2003 patent-related cases. We limited our analysis to the 345 cases in which the CAFC discussed the obviousness of the patented inventions.

Figure 1. The outcomes of the US Court of Appeals for Federal Circuit rulings that were decided from 2001 to April 2013.

The CAFC decisions on the obviousness of the invention in the suit included some obvious rulings, some non-obvious rulings, as well as a number of cases that were remanded for further proceedings. The obvious rulings included cases in which the CAFC affirmed the district court’s obviousness judgments or reversed the lower court’s non-obviousness conclusions, whereas the non-obvious rulings entailed the CAFC affirming the district court’s non-obviousness judgments or reversing the lower court’s obviousness conclusions.

To demonstrate the influence of the KSR case, we used the date of the case, April 30, 2007, as the cutoff point. Our analysis showed that the obvious ruling rate increased from 0.42 (47 out of 113 cases) to 0.52 (121 out of 232 cases) after the KSR case. Furthermore, the non-obvious ruling rate decreased from 0.47 (52 out of 113 cases) to 0.35 (81 out of 232 cases). Therefore, without the rigid application of a TSM test, the trends for obvious and non-obvious CAFC rulings increased and decreased, respectively. A chi-squared analysis showed that the differences in the two rates before and after KSR were statistically significant (P<0.05).

We further analyzed the biotech-related cases that were decided by the CAFC after KSR. The obvious ruling rate in these cases (49%, 23 out of 47 cases) appears notably lower than the average rate in the cases that involved the other technology fields (63%, 98 out of 155 cases). This finding is likely due to the diverse nature of biotech inventions, which are typically combinations of dissimilar elements or methods.⁷

During this analysis, we found a number of the key factors, which include the scope of the claims, the secondary considerations, the expectation of success and the motivation to select similarity, are highly correlated with the CAFC obvious decisions post-KSR. These opinions highlight the subjectivity of the determination of obviousness and can therefore serve as prediction factors for the prosecution and litigation of biotech patents.

Scope of the Claims

According to the patent statute, the claims define the metes and bounds of a patented invention.⁸ A claim would be obvious if the claim is drafted to cover the scope of prior art, regardless of whether the prior art solves the particular problem that is being addressed in the new claim. Even thought the claim presents an invention, which addresses a long-felt but unsolved need, the objective evidence of non-obviousness can still fail.

In the Therasense, Inc. v. Beckton, Dickinson and Co. case,⁹ the patent in the suit (U.S. patent 5 628 890) detailed the placement of the counter electrode downstream of the working electrode to measure the glucose levels in blood. This arrangement of the electrodes forces the blood into contact with the working electrode before it makes contact with the counter electrode. Thus, this new design prevents the blood from not being able to fully cover the working electrode, thereby solving the so-called “short-fill” problem that previously gave erroneously low glucose levels. However, the claims in the suit were not limited to the placement of the sensors that resulted in the prevention of the short-fill problem. Instead, the claims were broad enough to cover devices that either solve or do not solve this problem. Therefore, the CAFC affirmed that the objective evidence of non-obviousness failed because it was not commensurate in scope with the claims.

In the re Tzipori case,¹⁰ the application claimed the development of antibodies to Shiga-like toxin II (SLT-II), which upon injection bind to SLT-II and ameliorate its harmful effects. However, the application did not specify that the antibodies bind specifically to SLT-II, nor did the application clearly detail how or whether the claimed antibodies differ from antibodies that had been disclosed by prior art, which might be suitable for animal treatment. Furthermore, two separate instances of prior art cited the same references. The evidence supported that a person with an ordinary level skill in the field would obviously combine the references.

In the Chapman v. Casner case,¹¹ the patent application in the suit (U.S. publication 20060173029) disclosed that the oxidation of thebaine creates the 8α stereoisomer of 8,14-hydroxy, which in turn produces additional 14-hydroxy during the formulation of the pain medicine oxycodone salt. However, the claim did not differentiate between the 8α and 8β forms of 8,14-dihydroxy. Nor did the claim language specifically disclose which conditions were suitable for promoting the desired reaction from 8,14-dihydroxy to 14-hydroxy. The prior art expressly disclosed a species that was found within the subject matter that was claimed. Therefore, the reference was a technical anticipation of the claim.

Similarly, the CAFC also noted that the obviousness inquiry requires a review of the claimed sequence, not the appellants’ unclaimed cloning technique, which is obvious in light of the prior art.¹² In other words, even if an invention itself is patentable, the broadly drafted claims that cover the prior arts can render a claim obvious.

Secondary Considerations

The CAFC frequently stresses that the evidence of secondary considerations must always be considered in the determination of obviousness.¹³ Furthermore, the evidence of secondary considerations must be reasonably commensurate with the scope of the claims.¹⁴ The patentee or applicant must establish a nexus between the evidence of secondary consideration and the merits of the claimed invention.¹⁵

The demonstration of unexpected results as secondary considerations can avoid an obviousness rejection during the patent prosecution or invalidation during infringement litigation.⁵ Specifically, when the prior art has listed the claimed subject as one of the selections, the failure to present evidence of unexpected results can render the selection obvious.¹⁶ Moreover, the lack of demonstration of evidence that non-routine experimentation was required to create the claimed invention in the previous disclosure, regardless of whether it was recorded as a preferred embodiment, would render the claim obvious. It is well settled that all of the teachings that can be gained from a prior art reference and not just the embodiments disclosed must be considered in the determination of obviousness.¹⁷

The CAFC indicated that one of the fourteen ingredients can be anticipated, even though the prior art did not specially emphasize it.¹⁸ In addition, the disclosure of multiple combinations can render a particular formulation obvious.¹⁹ However, case law does not provide enough data to determine at which point, if any, the size of the genus would be unlikely to render the species obvious.²⁰ In general, the larger the genus, the less likely that a species within that genus will be held obvious, and vice versa.²⁰ The CAFC further emphasized that it is not the mere number of compounds, but the total circumstances involved that determine the obviousness of a claim.²¹ The key point is summarized by 35 U.S.C. §103, which states that “the difference between the subject matter sought to be patented and prior art are such the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art”.

In the Ortho-McNeil Pharmaceutical Inc. v. Teva Pharmaceuticals Ind. Ltd. case²², the patent in the suit (US patent 5 336 691) described that a composition of tramadol and acetaminophen has a synergistic effect. The difference between the claim and the prior art was the weight ratio. However, the evidence indicated that there was no perceptible difference in the synergy between weight ratio of 1:7.1 and 1:10. Therefore, the CAFC affirmed that the assignee failed to raise a genuine dispute of material fact regarding the obviousness of the claim.

Regarding the commercial success of secondary considerations, a patentee need not show that all possible embodiments within the claims were successfully commercialized to rely on the success in the marketplace of the embodiment that was commercialized.^23,24 In the re Huai-Hung Kao case,²⁵ the applicants’ expert opined that the unexpected in-vivo concentration and the improvement in analgesic tolerance were responsible for the commercial success of the embodying product. The CAFC therefore asked the US Board of Patent Appeals and Interferences to reconsider if the commercial success of the embodying product resulted from the merits of the claimed invention or other extrinsic factors. However, in the same case, an informing step was the only limitation of another claim that was not expressly recited in the prior art. The applicant failed to present that the evidence of commercial success was attributable to the informing step. In fact, the claim did not require that the informing step have any appreciable effect on the administration of the drug. Thus, the CAFC concluded that the secondary considerations did not compel a holding of nonobviousness, even though the applicant argued that the commercial success of the product would overcome the obviousness.

Reasonable Expectation of Success

In KSR International Co. v. Teleflex Inc.⁶ the Supreme Court indicated that, when there is a demand or market pressure to solve a problem and there are finite number of identified and predictable solutions, a person of ordinary skill has good reason to pursue the known option within her or his technical grasp.⁵ If this leads to the anticipated success, the result is likely the product of ordinary skill and common sense and not of invention. In other words, the obviousness of an invention highly depends on whether the prior art gives an expectation of success for the creation the invention.⁵

In the re Kubin case,¹² the appellants claimed DNA molecules that encode the protein Natural Killer Cell Activation Inducing Ligand (NAIL). The specification of the claimed invention disclosed the isolation and sequences of a polynucleotide that encodes the NAIL polypeptide. Moreover, the specification indicated that the nucleic acid molecule had been derived using standard biochemical methods. The evidence strongly supported that the appellants employed conventional methods to isolate a cDNA encoding NAIL and to determine its full nucleotide sequence. Therefore, the CAFC affirmed that a skilled artisan has a reasonable expectation of success in the derivation of the claimed invention in light of the teachings of the prior art.

In the Celsis In Vitro Inc. v. Cellzdirect Inc.case,²⁶ the invention under investigation disclosed methods for the preparation of multi-cryopreserved hepatocytes, which no other reference had revealed at the time of the invention. Moreover, prior evidence demonstrated that a single round of freezing severely damages hepatocytes and results in lower cell viability. A person of ordinary skill would expect that a second freezing of those damaged cells would kill even more cells than the first freezing. Therefore, the CAFC affirmed the nonobviousness decision because, regardless of the prior art suggested a method of multi-cryopreservation, the experts did not predict the results of the claimed methods at the time of the invention.

Reason or Motivation to Select and Modify the Structural Similarity

To establish a prima facie case of obviousness in cases involving new chemical compounds, the accused infringer must identify a reason that would have led a chemist to modify a known compound in a particular manner.²⁷ The existence of similar properties between the claimed and the prior art compounds can sufficiently demonstrate the motivation.²⁸ After KSR, the obviousness based on structural similarity still requires that the prior art gives a reason or motivation for the creation of the claimed compositions.^29,30 However, the reason or motivation need not be an explicit guarantee that the claimed compound will have a particular utility; it is sufficient to demonstrate that the claimed and the prior art compounds possess a close relationship to create an expectation of a specific property in the new compound.⁵

In Altana Pharma Ag v. Teva Pharmaceuticals USA Inc,³¹ the patent in the suit (US patent 4 758 579) concerned the compound pantoprazole, which is the active ingredient in an anti-ulcer drug. The compound in this litigation exhibited a structure that was very similar to a compound that was disclosed by another patent belonging to the same assignee. A person of skill in the art could select the modified compound as the eighteen compounds that were listed in previous patent. Moreover, qualified experts also supported the obviousness argument.

In the Bayer Schering Pharma AG v. Barr Laboratories Inc. case³², the patent in the suit (US patent 6 787 531) detailed the use of micronized drospirenone particles as a daily oral contraceptive. The prior arts disclosed the potential use of drospirenone with 17α-ethinylestradiol as an oral contraceptive and that micronization can improve the dissolution of drospirenone. The patent assignee’s own expert also testified that the micronization of the particles is the first choice in the improvement of this compound solution because it presents the best chance for success. The CAFC affirmed that a drug formulator with ordinary skill would consider micronized, unprotected drospirenone and would have a reasonable expectation that this chemical would perform similarly to spirorenone, which was disclosed in the prior art. However, it should be noted that a federal judge dissented with the majority opinions. The dissenting opinion argued that it was not reasonably expected that uncoated micronized drospirenone would be effective as an oral contraceptive when ingested into the acidic stomach because it was known to degrade rapidly in acid.

In the re Brimonidine patent litigation case,³³ the defendant contended that it would have been obvious to combine the Alphagan^® and Refresh Tears^® into a single formulation because both contains carboxymethylcellulose (CMC) and both were routinely prescribed together. The defendant claimed that the effect of combination would therefore have been obvious, which would render the asserted claims invalid for obviousness. However, although two ingredients might be therapeutically effective when used separately as part of an overall treatment regimen, the ingredients might be incompatible or ineffective when combined in a single solution. Furthermore, the evidence did not support that therapeutically effective concentrations of brimonidine would be soluble at the slightly alkaline pH range of Refresh Tears or that the CMC would act as a solubility enhancer. Therefore, the CAFC affirmed the nonobviousness decision.

Cases Related to Immunotherapy or Vaccines

Case 1

A study demonstrated that interleukin 13 (IL-13) receptor subunit alpha 2 (IL-13Rα2) is a cell-surface receptor, affording it exposure to the humoral arm of the immune system. Furthermore, IL-13Rα2 is expressed on the vast majority of high-grade gliomas (HGGs) tested, indicating its critical role in HGG progression and its potential as a target for immunotherapy. The physiological distribution of IL-13Rα2 is also limited to cancer cells and the testes, limiting the potential for autoimmune side effects that are observed when the target is also expressed in healthy tissue. Thus, the inventors claimed a method for stimulating an immune response against IL-13Rα2 in a subject having tumor cells expressing IL-13Rα2. The new immunotherapy comprised an agent with certain amino acid sequence or a protein fragment that can stimulate an immune response against IL-13Rα2.

The patent examiner found the first prior art which disclosed an administration of peptide with the same amino acid sequence for therapeutic treatment. The second prior art revealed administration of tumor-associated antigen peptides to treat cancer and measuring the immune response following administration of the tumor antigen peptide. The patent examiner pointed that one of ordinary skill in the art would have been motived to apply the second prior art for inducing immune response to a tumor antigen to the first prior art of administering the polypeptide with the same amino acid sequence. Thus, the patent application was rejected under 35 USA 103(a) as being obvious over these two prior arts.

The inventors argued that the first prior art only disclosed immune response in pathologies where IL-13 and IL-4 play a role and a method for the therapeutic treatment of conditions linked to immunological reactions mediated by IL-13, but not to cancer. The example cited by the patent examiner in the first prior art was about an effect of an antibody against one of the chains of a physiological receptor shared between IL-13 and IL-4. The disclosure was not even related to this patent application for stimulating an immune response against IL-13Rα2 involving administration of an anti-cancer vaccine.

Therefore, the combination of these two prior arts failed to teach or suggest all claim limitations and to implicitly or explicitly suggest modifying their teachings to arrive applicants’ invention. As mentioned above, there was no reason or motivation to select and modify the structural similarity and no reasonable expectation of success. The patent examiner accepted the augments and allowed this patent application.

Case 2

An invention disclosed a vaccine including a mixture of different nucleic acid constructs encoding antigenic polypeptides of multiple clades or strains of HIV to elicit immune responses against multiple variants of HIV. Each of multiple nucleic acid constructs were combined by encoding separate proteins into separate nucleic acid constructs. The nucleic acid constructs lack of fusion, unlike the HIV vaccines previously developed, had been modified to increased immunogenicity. Thus, the inventors claimed pharmaceutical compositions or medicament for the therapeutic or prophylactic treatment of an HIV infection.

The first prior art disclosed compositions that comprised one or more vectors encoding one or more HIV antigens derived from a variety of clades to broaden antiviral immune responses without immune interference. The second prior art revealed a prime-boost immunization to generate mutated HIV-1 env protein resulted in the induction of strong immune response. The patent examiner pointed out that one of ordinary skill in the art would have been incorporated the immunization regimen of the second prior art with the multiclade immunization protocol of first prior art. Therefore, the patent application was rejected under 35 USC §103 as being obvious over these two prior arts.

The inventors argued that neither the first prior art nor the second prior art disclosed a prime-boost HIV immunization strategy that involves administration of a composition comprising the same number of plasmids and vectors. Furthermore, the current patent application required a larger number of plasmids that stimulate significantly higher cellular immune responses as compared the composition of first prior art. However, the first prior art stated that compositions with lower complexity may be better candidates for clinical HIV vaccine development. Thus, one of ordinary skill in the art would not have reasonably expected that the composition described in the patent application would induce a more potent immune response than the previous composition.

Other than the first prior art teaching away from this patent application, this current patent application also demonstrated surprising or unexpected results in specification. Therefore, the application would not have been obvious to one of ordinary skill in the art in view of combination of prior art. The patent examiner then accepted the arguments and allowed the patent application.

Conclusion

In the KSR case,⁶ the US Supreme Court indicated that, when there is a design need or market pressure to solve a specific problem and there are a finite number of predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that the product is the result of ordinary skill and common sense and not of innovation. Furthermore, because progress at the higher levels of achievement is normally expected, the results of ordinary innovation are not the subject of exclusive rights under the patent laws.

After the KSR case, without the rigid application of a “teaching, suggestion, or motivation” test, the trends for obvious and non-obvious CAFC rulings significantly increased and decreased, respectively.⁵ However, due to the diverse nature of biotech inventions, the obvious ruling rate for biotech cases appears to be lower than in other technology fields. These opinions of CAFC highlight the subjective nature of obviousness and can therefore serve as prediction factors for prosecution and litigation of biotech patent.

For example, when the claims are broad enough to cover prior art, the objective evidence for answering a long-felt but unsolved need still can fail to demonstrate non-obviousness. Furthermore, when the prior art has listed the claimed subject as one of its selections, the failure to present evidence of unexpected results can render the selection obvious¹⁶. More particularly, the utilization of conventional methods to isolate a cDNA encoding a protein and to determine its full nucleotide sequence has a reasonable expectation of success, which makes the claimed invention obvious. The obviousness of a novel chemical compound that is based on structural similarity requires that the prior art provides a reason or motivation to make the claimed composition.^29,30 However, the reason or motivation does not need be an explicit guarantee that the claimed compound will have a particular utility. In fact, it is sufficient to demonstrate that the claimed and the prior art compounds possess a close relationship that would lead to expectation.

Based on this investigation, biotech inventors should contemplate the factors of obviousness that result in rulings of obviousness, which include claims that are too broad, the lack of secondary considerations, the reasonable expectation of success, and lack of a reason or motivation to create a particular structure based on structural similarity. The presence of any of these factors can result in the rejection of a claim during patent prosecution or in the invalidation of a claim in patent litigation. On the other hand, patent applicants may use these factors to overcome obviousness rejections as shown by the cases in this article related to immune therapy or vaccine.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.