IP Court Establishes Selection of Lead Compound and Motivation to Modify the Lead Compound Part II | Comparative Analysis across Taiwan, the United States, Europe and China

Date: 26 May 2022

In part I, we discussed the Taiwan IP court's opinion on "lead compound selection" and "motivation to modify a compound" in the case of Millennium Pharmaceuticals, Inc., Takeda Pharmaceuticals Taiwan Ltd. v. Chunghwa Compound Synthesis & Biotech Co., Ltd. (Taiwan IP Court 2021 MinZhuanSuZi No.19 Judgment). In part II, we will go deeper into the examination practices in Taiwan, the United States, Europe and China.

Comparative Analysis of Examination Practice on “Lead Compound Selection” and “Motivation to Modify a Compound” in Taiwan, the United States, Europe and China

1. Taiwan

Taiwan Patent Examination Guidelines do not explicitly stipulate the motivation to modify a compound. Whether a compound involves an inventive step / non-obviousness is determined primarily by structural similarity. If the claimed compound does not resemble the prior art compound, the claimed compound involves an inventive step. If the compounds are similar and have similar uses, in principle, the claimed compound does not involve an inventive step unless proven to have unexpected effects. This standard is the same as in China. Pertaining to structural similarity, the Patent Examination Guidelines state that molecular structure alone cannot determine the structural similarity between two compounds; other aspects such as the technical field, relevance of the structure and effect, scope of application must be considered.1

In the case of Millennium Pharmaceuticals, Inc., Takeda Pharmaceuticals Taiwan Ltd. v. Chunghwa Compound Synthesis & Biotech Co., Ltd. covered in part I, the Taiwan IP court ruled that lead compound selection must be similar in terms of structure as well as pharmacological action. Hindsight bias is likely to occur if only structural similarity but not pharmacological action is taken into consideration. In addition, the judgment specifically stated that "compounds which are selected as the lead compounds with reasonable motivation do not necessarily have the best effect."

2. The United States

The United States values lead compound selection. In numerous US patent invalidity cases, it was first examined whether a person having ordinary skill in the art (PHOSITA) was motivated to select the technical means disclosed by the invalidation petitioner to be the lead compound2 . The Court of Appeals for the Federal Circuit (CAFC) pointed out that, under usual circumstances, only “the compound with the most promising and useful properties” qualifies as a lead compound. A compound with known adverse effects (teaching away)3 or minimal structural difference from the claimed compound does not necessarily qualify as a lead compound. When the compound selected by the invalidation petitioner does not qualify as a lead compound, the compound at issue should be accredited with an inventive step.

The Lead Compound Analysis (LCA) was established by the US Federal Court in 2000 in Yamanouchi Pharm. Co. v. Danbury Pharmacal, Inc. LCA involves a two-step inquiry:

  1. Determine whether a PHOSITA would have selected a specific prior art compound as the lead compound or the starting point.
  2. Determine whether the prior art would have supplied a PHOSITA with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.

It should be noted that, to avoid hindsight bias in LCA, the prior art compound must have satisfactory properties for a PHOSITA to precisely select the compound as a starting point among the myriad of technical means disclosed in the prior art.

The CAFC's criteria for inventive step of chemical compounds in pharmaceutical patents are introduced in the following decision.

Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.4

Case Outline

The patent at issue (US05006528A; patentee: Otsuka Pharmaceutical Co., Ltd.) concerns a compound called Aripiprazole, which is used to treat a variety of mental disorders.

Sandoz argued that a PHOSITA would be motivated to select 2,3-dichloro propoxy, unsubstituted butoxy, and OPC-4392 from the prior art as the starting point, shown sequentially as follows:

And through simple substitution or displacement, Aripiprazole is obtained. Sandoz alleged that the above compounds resemble Aripiprazole, so a PHOSITA would be motivated to select them as the lead compound.

The Court’s Opinion

The CAFC considered that 2,3-dichloro propoxy was merely one of the hundreds of compounds having central nervous controlling action in the examples; though the prior art disclosed the mouse jumping data of the unsubstituted butoxy, four other compounds were significantly superior to the unsubstituted butoxy. Literature also showed that the activity of OPC-4392 was not high and it caused severe side effects like visual hallucination and delusion, thus, according to the teaching of prior art, a PHOSITA would not have selected the above compounds as the lead compound.

Following lead compound selection, whether there exists any motivation or teaching to modify a lead compound is also valued in the process. The motivation to modify should have reasonable expectation of success, that is, it is anticipated that the modification can improve activity or fix the known flaws of an existing compound without sacrificing its advantages. Thus, motivation to modify cannot be based simply on hypothetical or broad structural approximations but explicit scientific basis or experimental evidence.

The practice of Europe and China will be covered in part III.

[1]Taiwan Patent Examination Guidelines Part II, chapter 13

[2]Yamanouchi Pharmaceutical v. Danbury Pharmacal, 21 F. Supp. 2d 366 (S.D.N.Y. 1998); Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012); Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. (Fed. Cir. 2007); Bristol-Myers Squibb Company v. Teva Pharmaceuticals USA, Inc., No. 2013-1306 (Fed. Cir. June 12, 2014).

[3]Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. (Fed. Cir. 2007)

[4]Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280 (Fed. Cir. 2012)

 

 

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